Itsuro Endo and Toshio Matsumoto : [Hormones and osteoporosis update. Vitamin D and bone]., Jul. 2009.
(Summary)
Calcium homeostasis is maintained by parathyroid hormone and vitamin D. Mechanisms of action of these calcium-regulating hormones have been extensively examined, and the intracellular signaling pathways as well as transcriptional regulation of their target genes have been elucidated. Epidemiological studies revealed the importance of vitamin D sufficiency, and efforts have been made to implement the diagnostic criteria for vitamin D insufficiency. As a therapeutic agent, a new active vitamin D analog with anti-fracture efficacy has been developed for the treatment of osteoporosis.
(Keyword)
Accidental Falls / Calcium / Drug Design / Homeostasis / Humans / Osteoporosis / RANK Ligand / Receptors, Calcitriol / Retinoid X Receptors / Signal Transduction / Transcription, Genetic / Vitamin D / Vitamin D Deficiency
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 19567986
Toshihiro Hashimoto, Masahiro Abe and Toshio Matsumoto : [Biochemical markers in bone metastasis]., 癌と化学療法社, Tokyo, Jul. 2004.
(Summary)
Certain types of cancers have a strong propensity to metastasize to bone, which requires combination of multiple factors responsible for the different steps of metastasis. Bone metabolic markers are now widely used in clinical practice and give useful information on the ongoing bone metabolism, reflecting the activity of bone-resorbing osteoclasts and bone-forming osteoblasts. Bone markers have a potential as diagnostic tools for bone metastasis, and are useful in monitoring the response to anticancer as well as antiresorptive therapies. Since bone metabolic markers alone are insufficient for the diagnosis and assessment of bone metastasis, it is important to combine bone markers with tumor-related markers and imaging studies such as scintigraphy and MRI. More recently, soluble receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG) have been implicated as markers for osteoclastogenic activity. Serum levels of these factors and/or their ratios may provide additional information on the severity of bone disease and the prognosis.
(Keyword)
bone metastasis / Bone markers / Osteoclastogenesis
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 15272580
Yuichi Takashi, Hidetaka Kosako, Shun Sawatsubashi, Yuka Kinoshita, Nobuaki Ito, Maria K. Tsoumpra, Masaomi Nangaku, Masahiro Abe, Munehide Matsuhisa, Shigeaki Kato, Toshio Matsumoto and Seiji Fukumoto : Activation of unliganded FGF receptor by extracellular phosphate potentiates proteolytic protection of FGF23 by its O-glycosylation, Proceedings of the National Academy of Sciences of the United States of America, 2019.
(Summary)
Fibroblast growth factor (FGF) 23 produced by bone is a hormone that decreases serum phosphate (Pi). Reflecting its central role in Pi control, serum FGF23 is tightly regulated by serum Pi alterations. FGF23 levels are regulated by the transcriptional event and posttranslational cleavage into inactive fragments before its secretion. For the latter, O-glycosylation of FGF23 by gene product prevents the cleavage, leading to an increase in serum FGF23. However, the molecular basis of Pi sensing in the regulation of serum FGF23 remains elusive. In this study, we showed that high Pi diet enhanced the skeletal expression of , but not , with expected increases in serum FGF23 and Pi in mice. induction by high Pi was further observed in osteoblastic UMR 106 cells, and this was mediated by activation of the extracellular signal-regulated kinase (ERK) pathway. Through proteomic searches for the upstream sensor for high Pi, we identified one subtype of the FGF receptor (FGFR1c), which was phosphorylated by high Pi in the absence of FGFs. The mode of unliganded FGFR activation by high Pi appeared different from that of FGFR bound to a canonical FGFR ligand (FGF2) when phosphorylation of the FGFR substrate 2α and ERK was monitored. Finally, we showed that an FGFR inhibitor and conditional deletion of in osteoblasts/osteocytes abrogated high Pi diet-induced increases in serum FGF23 and femoral expression in mice. Thus, these findings uncover an unrecognized facet of unliganded FGFR function and illustrate a Pi-sensing pathway involved in regulation of FGF23 production.
Shun Sawatsubashi, Yudai Joko, Seiji Fukumoto, Toshio Matsumoto and Shigeo S. Sugano : Development of versatile non-homologous end joining-based knock-in module for genome editing., Scientific Reports, Vol.8, No.1, 593, 2018.
(Summary)
CRISPR/Cas9-based genome editing has dramatically accelerated genome engineering. An important aspect of genome engineering is efficient knock-in technology. For improved knock-in efficiency, the non-homologous end joining (NHEJ) repair pathway has been used over the homology-dependent repair pathway, but there remains a need to reduce the complexity of the preparation of donor vectors. We developed the versatile NHEJ-based knock-in module for genome editing (VIKING). Using the consensus sequence of the time-honored pUC vector to cut donor vectors, any vector with a pUC backbone could be used as the donor vector without customization. Conditions required to minimize random integration rates of the donor vector were also investigated. We attempted to isolate null lines of the VDR gene in human HaCaT keratinocytes using knock-in/knock-out with a selection marker cassette, and found 75% of clones isolated were successfully knocked-in. Although HaCaT cells have hypotetraploid genome composition, the results suggest multiple clones have VDR null phenotypes. VIKING modules enabled highly efficient knock-in of any vectors harboring pUC vectors. Users now can insert various existing vectors into an arbitrary locus in the genome. VIKING will contribute to low-cost genome engineering.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) agonists induce tumor-specific apoptosis indicating that they may be an attractive therapeutic strategy against cancers, including multiple myeloma (MM). Osteoclastogenesis is highly induced in MM, which in turn enhances MM growth, thereby forming a vicious cycle between MM tumor expansion and bone destruction. However, the effects of TRAIL on MM-enhanced osteoclastogenesis remain largely unknown. Here, we show that TRAIL induced apoptosis in MM cells, but not in osteoclasts (OCs), and that it rather facilitated receptor activator of NF-B ligand-induced osteoclastogenesis along with upregulation of cellular FLICE inhibitory protein (c-FLIP). TRAIL did not induce death-inducing signaling complex formation in OCs, but formed secondary complex (complex II) with the phosphorylation of transforming growth factor -activated kinase-1 (TAK1), and thus activated NF-B signaling. c-FLIP knockdown abolished complex II formation, thus permitting TRAIL induction of OC cell death. The TAK1 inhibitor LLZ1640-2 abrogated the TRAIL-induced c-FLIP upregulation and NF-B activation, and triggered TRAIL-induced caspase-8 activation and cell death in OCs. Interestingly, the TRAIL-induced caspase-8 activation caused enzymatic degradation of the transcription factor Sp1 to noticeably reduce c-FLIP expression, which further sensitized OCs to TRAIL-induced apoptosis. Furthermore, the TAK1 inhibition induced antiosteoclastogenic activity by TRAIL even in cocultures with MM cells while potentiating TRAIL's anti-MM effects. These results demonstrated that osteoclastic lineage cells use TRAIL for their differentiation and activation through tilting caspase-8-dependent apoptosis toward NF-B activation, and that TAK1 inhibition subverts TRAIL-mediated NF-B activation to resume TRAIL-induced apoptosis in OCs while further enhancing MM cell death in combination with TRAIL.
Takeshi Mitsuhashi, Ryoko Uemoto, Kazue Ishikawa, Sumiko Yoshida, Yasumasa Ikeda, Shusuke Yagi, Toshio Matsumoto, Masashi Akaike and Ken-ichi Aihara : Endothelial Nitric Oxide Synthase-Independent Pleiotropic Effects of Pitavastatin Against Atherogenesis and Limb Ischemia in Mice., Journal of Atherosclerosis and Thrombosis, 2017.
(Summary)
Pitavastatin exerts eNOS-independent protective effects against atherogenesis and hind-limb ischemia in mice, which may occur via modifications on key molecules such as AMPK and diverse molecules.
Kiyoe Kurahashi, Seika Inoue, Sumiko Yoshida, Yasumasa Ikeda, Kana Morimoto, Ryoko Uemoto, Kazue Ishikawa, Takeshi Kondo, Tomoyuki Yuasa, Itsuro Endo, Masato Miyake, Seiichi Oyadomari, Toshio Matsumoto, Masahiro Abe, Hiroshi Sakaue and Ken-ichi Aihara : The Role of Heparin Cofactor in the Regulation of Insulin Sensitivity and Maintenance of Glucose Homeostasis in Humans and Mice., Journal of Atherosclerosis and Thrombosis, 2017.
(Summary)
The present studies provide evidence to support the idea that HC plays an important role in the maintenance of glucose homeostasis by regulating insulin sensitivity in both humans and mice. Stimulators of HC production may serve as novel therapeutic tools for the treatment of type 2 diabetes.
Akio Kuroda, Tsuruo Miho, Aki Nanako, Takeshi Kondo, Oguro Yukari, Motoyuki Tamaki, Ken-ichi Aihara, Itsuro Endo, Toshio Matsumoto, Masahiro Abe and Munehide Matsuhisa : A Pirot study comparing the CGM-assessed glycemic profiles of patients with type 1 diabetes on insulin degludec and insulin glargine, Diabetology International, Vol.8, No.1, 112-115, 2017.
Myeloma (MM) cells and osteoclasts are mutually interacted to enhance MM growth while creating acidic bone lesions. Here, we explored acid sensing of MM cells and its role in MM cell response to acidic conditions. Acidic conditions activated the PI3K-Akt signaling in MM cells while upregulating the pH sensor transient receptor potential cation channel subfamily V member 1 (TRPV1) in a manner inhibitable by PI3K inhibition. The acid-activated PI3K-Akt signaling facilitated the nuclear localization of the transcription factor Sp1 to trigger the expression of its target genes, including TRPV1 and HDAC1. Consistently, histone deacetylation was enhanced in MM cells in acidic conditions, while repressing a wide variety of genes, including DR4. Indeed, acidic conditions deacetylated histone H3K9 in a DR4 gene promoter and curtailed DR4 expression in MM cells. However, inhibition of HDAC as well as either Sp1 or PI3K was able to restore DR4 expression in MM cells suppressed in acidic conditions. These results collectively demonstrate that acid activates the TRPV1-PI3K-Akt-Sp1 signaling in MM cells while inducing HDAC-mediated gene repression, and suggest that a positive feedback loop between acid sensing and the PI3K-Akt signaling is formed in MM cells, leading to MM cell response to acidic bone lesions.
Takeshi Kondo, Itsuro Endo, Ken-ichi Aihara, Ohnishi Yukiyo, Dong Bingzi, Oguro Yukari, Kiyoe Kurahashi, Sumiko Yoshida, Yuichi Fujinaka, Akio Kuroda, Munehide Matsuhisa, Seiji Fukumoto, Toshio Matsumoto and Masahiro Abe : Serum carboxy-terminal telopeptide of type I collagen levels are associated with carotid atherosclerosis in patients with cardiovascular risk factors., Endocrine Journal, Vol.63, No.4, 397-404, 2016.
(Summary)
Carboxy-terminal telopeptide of type I collagen (ICTP) is generated through matrix metalloproteinase (MMP)-dependent type I collagen digestion, and has been widely utilized as a biomarker for bone turnover. The fact that atherosclerotic lesions are rich in both type I collagen and MMP-producing macrophages led to the hypothesis that serum ICTP concentrations may serve as a non-invasive clinical biomarker for atherosclerosis. Therefore, the association of serum ICTP concentrations with the maximum intima-media thickness (IMT) of carotid arteries, a surrogate index of systemic atherosclerosis, or brachial-ankle pulse wave velocity (baPWV) in patients with atherosclerotic risk factors was evaluated. A total of 52 male and 65 female (mean age: 62.8 yrs) patients without renal failure, malignancies or bone diseases known to affect serum ICTP concentrations were recruited. Patients with max IMTs ≥1.1 mm showed significantly higher serum ICTP concentrations compared with patients with max IMTs <1.1 mm (3.33 ± 0.97 vs 2.82 ± 0.65 ng/mL, p<0.05). Serum ICTP concentration was also positively correlated with max IMT (p<0.001) or baPWV values (p<0.05). Multivariate analyses also revealed that serum ICTP concentrations were correlated with max IMT (p<0.001; 95% CI 0.200 to 0.454). These results suggest that serum ICTP concentrations can be used as a non-invasive biomarker for systemic atherosclerosis.
James Derek Hanson, Shingen Nakamura, Ryota Amachi, Masahiro Hiasa, Asuka Oda, Daisuke Tsuji, Kohji Itoh, Takeshi Harada, Kazuki Horikawa, Jumpei Teramachi, Hirokazu Miki, Toshio Matsumoto and Masahiro Abe : Effective impairment of myeloma cells and their progenitors by blockade of monocarboxylate transportation., Oncotarget, Vol.6, No.32, 33568-33586, 2015.
(Summary)
Cancer cells robustly expel lactate produced through enhanced glycolysis via monocarboxylate transporters (MCTs) and maintain alkaline intracellular pH. To develop a novel therapeutic strategy against multiple myeloma (MM), which still remains incurable, we explored the impact of perturbing a metabolism via inhibiting MCTs. All MM cells tested constitutively expressed MCT1 and MCT4, and most expressed MCT2. Lactate export was substantially suppressed to induce death along with lowering intracellular pH in MM cells by blockade of all three MCT molecules with -cyano-4-hydroxy cinnamate (CHC) or the MCT1 and MCT2 inhibitor AR-C155858 in combination with MCT4 knockdown, although only partially by knockdown of each MCT. CHC lowered intracellular pH and severely curtailed lactate secretion even when combined with metformin, which further lowered intracellular pH and enhanced cytotoxicity. Interestingly, an ambient acidic pH markedly enhanced CHC-mediated cytotoxicity, suggesting preferential targeting of MM cells in acidic MM bone lesions. Furthermore, treatment with CHC suppressed hexokinase II expression and ATP production to reduce side populations and colony formation. Finally, CHC caused downregulation of homing receptor CXCR4 and abrogated SDF-1-induced migration. Targeting tumor metabolism by MCT blockade therefore may become an effective therapeutic option for drug-resistant MM cells with elevated glycolysis.
Shusuke Yagi, Ken-ichi Aihara, Masashi Akaike, Daiju Fukuda, HM Salim, Masayoshi Ishida, Tomomi Matsuura, Takayuki Ise, Koji Yamaguchi, Takashi Iwase, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Michio Shimabukuro, Toshio Matsumoto and Masataka Sata : Predictive factors for efficacy of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes mellitus., Diabetes & Metabolism Journal, Vol.39, No.4, 342-347, 2015.
(Summary)
BACKGROUND: Predictive factors for the efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors for lowering glycosylated hemoglobin (HbA1c) remain unclear in patients with type 2 diabetes mellitus. The aim of this study is therefore to clarify predictive factors of the efficacy of DPP-4 inhibitors for lowering HbA1c after 12 months of treatment.METHODS: A total of 191 consecutive type 2 diabetic patients (male sex 55%, mean age, 68.3±35.8 years), who had been treated with DPP-4 inhibitors for 12 months, were enrolled in this study and evaluated retrospectively.RESULTS: After 12 months of DPP-4 inhibitor treatment, random blood glucose level, and HbA1c level, decreased from 167±63 to 151±49 mg/dL (P<0.01), and from 7.5%±1.3% to 6.9%±0.9% (P<0.01) respectively, without severe side effects. Multiple regression analysis showed that predictors of DPP-4 inhibitor treatment efficacy in lowering HbA1c level after 12 months were a decrease in HbA1c level after 3 months of treatment, a high baseline HbA1c level, a low baseline body mass index, and the absence of coronary artery disease.CONCLUSION: Most suitable candidates for treatment with DPP-4 inhibitors are diabetics who are not obese and do not have coronary artery disease. In addition, long-term efficacy of DPP-4 inhibitors can be predicted by decrement of HbA1c after 3 months of treatment.
Seiji Fukumoto, Keiichi Ozono, Toshimi Michigami, Masanori Minagawa, Ryo Okazaki, Toshitsugu Sugimoto, Yasuhiro Takeuchi and Toshio Matsumoto : Pathogenesis and diagnostic criteria for rickets and osteomalacia-proposal by an expert panel supported by the Ministry of Health, Labour and Welfare, Japan, the Japanese Society for Bone and Mineral Research, and the Japan Endocrine Society., Journal of Bone and Mineral Metabolism, Vol.33, No.5, 467-473, 2015.
(Summary)
Rickets and osteomalacia are diseases characterized by impaired mineralization of bone matrix. Recent investigations have revealed that the causes of rickets and osteomalacia are quite variable. Although these diseases can severely impair the quality of life of affected patients, rickets and osteomalacia can be completely cured or at least respond to treatment when properly diagnosed and treated according to the specific causes. On the other hand, there are no standard criteria to diagnose rickets or osteomalacia nationally and internationally. Therefore, we summarize the definition and pathogenesis of rickets and osteomalacia, and propose diagnostic criteria and a flowchart for the differential diagnosis of various causes of these diseases. We hope that these criteria and the flowchart are clinically useful for the proper diagnosis and management of these diseases.
Bingzi Dong, Itsuro Endo, Yukiyo Ohnishi, Takeshi Kondo, Tomoka Hasegawa, Norio Amizuka, Hiroshi Kiyonari, Go Shioi, Masahiro Abe, Seiji Fukumoto and Toshio Matsumoto : Calcilytic Ameliorates Abnormalities of Mutant Calcium-Sensing Receptor (CaSR) Knock-In Mice Mimicking Autosomal Dominant Hypocalcemia (ADH)., Journal of Bone and Mineral Research, Vol.30, No.11, 1980-1993, 2015.
(Summary)
Activating mutations of calcium-sensing receptor (CaSR) cause autosomal dominant hypocalcemia (ADH). ADH patients develop hypocalcemia, hyperphosphatemia, and hypercalciuria, similar to the clinical features of hypoparathyroidism. The current treatment of ADH is similar to the other forms of hypoparathyroidism, using active vitamin D3 or parathyroid hormone (PTH). However, these treatments aggravate hypercalciuria and renal calcification. Thus, new therapeutic strategies for ADH are needed. Calcilytics are allosteric antagonists of CaSR, and may be effective for the treatment of ADH caused by activating mutations of CaSR. In order to examine the effect of calcilytic JTT-305/MK-5442 on CaSR harboring activating mutations in the extracellular and transmembrane domains in vitro, we first transfected a mutated CaSR gene into HEK cells. JTT-305/MK-5442 suppressed the hypersensitivity to extracellular Ca(2+) of HEK cells transfected with the CaSR gene with activating mutations in the extracellular and transmembrane domains. We then selected two activating mutations locating in the extracellular (C129S) and transmembrane (A843E) domains, and generated two strains of CaSR knock-in mice to build an ADH mouse model. Both mutant mice mimicked almost all the clinical features of human ADH. JTT-305/MK-5442 treatment in vivo increased urinary cAMP excretion, improved serum and urinary calcium and phosphate levels by stimulating endogenous PTH secretion, and prevented renal calcification. In contrast, PTH(1-34) treatment normalized serum calcium and phosphate but could not reduce hypercalciuria or renal calcification. CaSR knock-in mice exhibited low bone turnover due to the deficiency of PTH, and JTT-305/MK-5442 as well as PTH(1-34) increased bone turnover and bone mineral density (BMD) in these mice. These results demonstrate that calcilytics can reverse almost all the phenotypes of ADH including hypercalciuria and renal calcification, and suggest that calcilytics can become a novel therapeutic agent for ADH.
Itsuro Endo, Seiji Fukumoto, Keiichi Ozono, Noriyuki Namba, Daisuke Inoue, Ryo Okazaki, Mika Yamauchi, Toshitsugu Sugimoto, Masanori Minagawa, Toshimi Michigami, Masaki Nagai and Toshio Matsumoto : Nationwide survey of fibroblast growth factor 23 (FGF23)-related hypophosphatemic diseases in Japan: prevalence, biochemical data and treatment., Endocrine Journal, Vol.62, No.9, 811-816, 2015.
(Summary)
A nationwide epidemiologic survey of fibroblast growth factor 23 (FGF23)-related hypophosphatemic diseases was conducted in 2010 to clarify the prevalence and the clinical presentations of the disorders. A questionnaire inquiring the experience of patients with these diseases was sent to randomly selected hospitals throughout Japan. The estimated annual incidence of the diseases was 117 cases (95% CI 75 - 160), 55 males (95% CI 30 - 81) and 62 females (95% CI 40 - 84). Tumor-induced osteomalacia (TIO) and X-linked hypophosphatemic rickets (XLH) were the most prevalent causes of acquired and genetic FGF23-related hypophosphatemic diseases, respectively. The estimated incidence of XLH was about 1 in 20,000. We have also collected clinical data of the patients by a secondary survey. These patients showed FGF23 levels of above 30 pg/ml by intact assay in the presence of hypophosphatemia. While complete resection of responsible tumors improved biochemical abnormalities in patients with TIO, treatment with phosphate and/or active vitamin D3 did not normalize serum phosphate and tubular maximum transport of phosphate in patients with XLH. Our results suggest that there is no racial difference in the incidence of XLH. While FGF23 measurement is useful for the diagnosis of FGF23-related hypophosphatemic diseases, the better management is necessary especially for patients with genetic hypophosphatemic rickets caused by excessive actions of FGF23.
Shusuke Yagi, M Fujimura, Masashi Akaike, Ken-ichi Aihara, Takashi Iwase, M Tada, Yuka Ueda, Takayuki Ise, Koji Yamaguchi, Tetsuzo Wakatsuki, Toshio Matsumoto and Masataka Sata : Increase in serum triglyceride was associated with coronary plaque vulnerability in a patient with rheumatoid arthritis., Journal of Cardiology Cases, Vol.10, No.2, 54-57, 2014.
(Summary)
Rates of morbidity and mortality from cardiovascular disease are high in patients with rheumatoid arthritis (RA); however, the mechanisms and biomarkers that reflect coronary plaque vulnerability have not yet been established. We present a case of acute coronary syndrome (ACS) presumably caused by exacerbation of chronic inflammation of RA, in which an abrupt increase in serum triglyceride was seen on the day of onset of ACS but not during effort angina. This case suggests that RA patients with an abrupt increase in triglyceride need intensive care including anti-platelet and statin therapy for the prevention of coronary plaque rupture.<Learning objective: Triglyceride might be a sensitive biomarker of activated macrophages and plaque vulnerability in patients with RA. RA patients with an abrupt increase in triglyceride might need intensive care including anti-platelet and statin therapy for the prevention of coronary plaque rupture.>
Shusuke Yagi, Ken-ichi Aihara, Takeshi Kondo, Itsuro Endo, Junko Hotsuchi, Takayuki Ise, Takashi Iwase, Masashi Akaike, Toshio Matsumoto and Masataka Sata : High serum parathyroid hormone and calcium are risk factors for hypertension in Japanese patients., Endocrine Journal, Vol.61, No.7, 727-733, 2014.
(Summary)
Excess parathyroid hormone (PTH), known as primary hyperparathyroidism (pHPT), results in hypercalcemia and bone loss. Recent studies have shown that PTH is associated with the occurrence of hypertension in Western countries; however, controversy remains regarding high serum levels of PTH and calcium as risk factors for hypertension in Japanese patients. We retrospectively enrolled 114 consecutive Japanese patients who visited our hospital for examination and treatment of hypercalcemia and/or hypertension with serum calcium levels ≥ 9.8 mg/dL. To estimate the prevalence of hypertension, the patients were categorized according to calcium levels into hypercalcemic (10.2-13.4 mg/dL) and normocalcemic (9.8-10.1 mg/dL) groups, which were further categorized into high PTH (50-440 pg/mL) and low PTH (8-49 pg/mL) groups. The prevalence of hypertension was higher in patients with hypercalcemia than in patients with normocalcemia in both the high and low PTH groups. The prevalence of hypertension was higher in patients with high serum PTH levels than in patients with low serum PTH levels in both the hypercalcemic and normocalcemic groups. Logistic multiple regression analysis determined that serum calcium (P < 0.05) and PTH (P < 0.01) levels were positive contributors to hypertension. In conclusion, high serum levels of PTH and calcium are risk factors for hypertension in Japanese patients.
Koichiro Hayashi, Michihiro Nakamura, Hirokazu Miki, Shuji Ozaki, Masahiro Abe, Toshio Matsumoto, Sakamoto Wataru, Yogo Toshinobu and Kazunori Ishimura : Magnetically Responsive Smart Nanoparticles for Cancer Treatment with a Combination of Magnetic Hyperthermia and Remote-Control Drug Release, Theranostics, Vol.4, No.8, 834-844, 2014.
(Summary)
We report the synthesis of smart nanoparticles (NPs) that generate heat in response to an alternating current magnetic field (ACMF) and that sequentially release an anticancer drug (doxorubicin, DOX). We further study the in vivo therapeutic efficacy of the combination of magnetic hyperthermia (MHT) and chemotherapy using the smart NPs for the treatment of multiple myeloma. The smart NPs are composed of a polymer with a glass-transition temperature (T g) of 44°C, which contains clustered Fe3O4 NPs and DOX. The clustered Fe3O4 NPs produce heat when the ACMF is applied and rise above 44°C, which softens the polymer phase and leads to the release of DOX. The combination of MHT and chemotherapy using the smart NPs destroys cancer cells in the entire tumor and achieves a complete cure in one treatment without the recurrence of malignancy. Furthermore, the smart NPs have no significant toxicity.
(Keyword)
Animals / Body Weight / Drug Liberation / Female / Hyperthermia, Induced / Magnetic Phenomena / Mice / Nanoparticles / Neoplasms / Organ Size / Telemedicine
Masahiro Hiasa, Jumpei Teramachi, A Oda, Ryota Amachi, T Harada, Shingen Nakamura, Hirokazu Miki, Shiroh Fujii, Kumiko Kagawa, Keiichiro Watanabe, Itsuro Endo, Y Kuroda, T Yoneda, Daisuke Tsuji, Michiyasu Nakao, Eiji Tanaka, Kenichi Hamada, Shigeki Sano, Kouji Itou, Toshio Matsumoto and Masahiro Abe : Pim-2 kinase is an important target of treatment for tumor progression and bone loss in myeloma., Leukemia, 2014.
(Summary)
Pim-2 kinase is overexpressed in multiple myeloma (MM) cells to enhance their growth and survival, and regarded as a novel therapeutic target in MM. However, the impact of Pim-2 inhibition on bone disease in MM remains unknown. We demonstrated here that Pim-2 expression was also upregulated in bone marrow stromal cells and MC3T3-E1 preosteoblastic cells in the presence of cytokines known as the inhibitors of osteoblastogenesis in MM, including interleukin-3 (IL-3), IL-7, tumor necrosis factor-, transforming growth factor- (TGF-) and activin A, as well as MM cell conditioned media. The enforced expression of Pim-2 abrogated in vitro osteoblastogenesis by BMP-2, which suggested Pim-2 as a negative regulator for osteoblastogenesis. Treatment with Pim-2 short-interference RNA as well as the Pim inhibitor SMI-16a successfully restored osteoblastogenesis suppressed by all the above inhibitory factors and MM cells. The SMI-16a treatment potentiated BMP-2-mediated anabolic signaling while suppressing TGF- signaling. Furthermore, treatment with the newly synthesized thiazolidine-2,4-dione congener, 12a-OH, as well as its prototypic SMI-16a effectively prevented bone destruction while suppressing MM tumor growth in MM animal models. Thus, Pim-2 may have a pivotal role in tumor progression and bone loss in MM, and Pim-2 inhibition may become an important therapeutic strategy to target the MM cell-bone marrow interaction.Leukemia advance online publication, 30 May 2014; doi:10.1038/leu.2014.147.
Multiple myeloma (MM) remains incurable despite recent advances in the treatment of MM. Although the idea of MM cancer stem cells (CSCs) has been proposed for the drug resistance in MM, MM CSCs have not been properly defined yet. Besides clonotypic B cells, phenotypically distinct MM plasma cell fractions have been demonstrated to possess a clonogenic capacity, leading to long-lasting controversies regarding the cells of origin in MM or MM-initiating cells. However, MM CSCs may not be a static population and survive as phenotypically and functionally different cell types via the transition between stem-like and non-stem-like states in local microenvironments, as observed in other types of cancers. Targeting MM CSCs is clinically relevant, and different approaches have been suggested to target molecular, metabolic and epigenetic signatures, and the self-renewal signaling characteristic of MM CSC-like cells.
Mizuho Kinouchi, Ken-ichi Aihara, Yuichi Fujinaka, Sumiko Yoshida, Yukari Ooguro, Kiyoe Kurahashi, Takeshi Kondo, Nanako Aki, Akio Kuroda, Itsuro Endo, Munehide Matsuhisa and Toshio Matsumoto : Diabetic conditions differentially affect the endothelial function, arterial stiffness and carotid atherosclerosis., Journal of Atherosclerosis and Thrombosis, Vol.21, No.5, 486-500, 2014.
(Summary)
Aim: The levels of fasting and postprandial plasma glucose, HbA1c and other risk factors for atherosclerosis have distinct effects in patients with and those without diabetes mellitus. The aim of this study was to determine the impact of diabetic surrogate markers on the endothelial function, arterial stiffness and carotid atherosclerosis in individuals with and without diabetes. Methods: A total of 320 Japanese subjects(mean age: 61.2±12.1 years) were recruited in this study. Demographic, clinical and laboratory parameters, including 75 g OGTT(155 subjects) results, were examined. The endothelial function was evaluated according to the flow-mediated vasodilation of the brachial artery(%FMD). In addition, arterial stiffness was evaluated according to the brachial-ankle pulse wave velocity(baPWV), and carotid atherosclerotic changes were estimated according to the maximum intima-media thickness(max-IMT) and resistive index of the common carotid artery(CCA-RI). A multiple regression analysis was performed to identify independent determinants of these vascular surrogate markers. Results: None of the glucose-related parameters were associated with the %FMD. In contrast, the presence of T2DM, the HbA1c level and an increased plasma glucose level at 60 minutes during 75 g OGTT were associated with an increased baPWV. The HbA1c level was also correlated with an increased max-IMT. The fasting plasma glucose(FPG) level and the presence of T2DM correlated with an increased CCA-RI. In the subjects with T2DM, the protective effects of high-density lipoprotein cholesterol(HDL-C) on the %FMD and baPWV were abolished. Conclusions: Various glucose metabolism parameters have different effects the degree of arterial stiffness and presence of carotid atherosclerosis, but not the endothelial function, suggesting that pharmacological intervention has the potential to preserve the endothelial function in diabetic individuals. In addition, the presence of T2DM blunts the vascular protective effects of HDL-C on the endothelial function and progression of arterial stiffness.
(Keyword)
Type 2 diabetes / Endothelial function / Arterial stiffness / Carotid atherosclerosis
Takeshi Kondo, Akio Kuroda, 曽我部 公子, 大黒 由加里, 倉橋 清衛, Motoyuki Tamaki, Mizuho Kinouchi, Sumiko Yoshida, 安芸 菜奈子, Itsuro Endo, Ken-ichi Aihara, Yuichi Fujinaka, Munehide Matsuhisa and Toshio Matsumoto : Comparison of Continuous Glucose Monitoring (CGM) Values before and after Adrenalectomy in a Case of Adrenaline-producing Pheochromocytoma, Journal of the The Japan Diabetes Society, Vol.57, No.9, 729-735, 2014.
(Summary)
A 77-year-old woman was incidentally found to have a left adrenal mass measuring 2.5 cm in January 2012. The urine metanephrine concentration was 3.0 mg/day (normal range, 0.04-0.19 mg/day), and an iodine-131 metaiodobenzylguanidine (MIBG) scan showed uptake in the area of the left adrenal gland, leading to a diagnosis of pheochromocytoma. In addition, the patient had a history of diabetes mellitus for nine years, with gradually worsening blood glucose control since 2010. The patient was subsequently admitted to our hospital for perioperative care. On admission, her fasting blood glucose level was 121 mg/dl and her HbA1c level was 8.5 %. She was treated with basal-bolus insulin therapy during hospitalization and underwent adrenalectomy at the urology department after her glycemic control had improved. The total daily insulin dose was immediately decreased from 50 to 14 units after the adrenalectomy procedure. In addition, the mean glucose level on preoperative continuous glucose monitoring (CGM) had been 141 mg/dl with a standard deviation (SD) of 54. However, after the operation, the mean glucose level increased to 153 mg/dl while the SD decreased to 24; thus, the range of glycemic fluctuation markedly decreased after surgery. Therefore, excess endogenous adrenalin primarily contributed to the glycemic fluctuations observed in this patient with pheochromocytoma.
Takeshi Harada, Shuji Ozaki, Asuka Oda, Daisuke Tsuji, Akishige Ikegame, Masami Iwasa, Kengo Udaka, Shiroh Fujii, Shingen Nakamura, Hirokazu Miki, Kumiko Kagawa, Yoshiaki Kuroda, Shigeto Kawai, Kouji Itou, Hisafumi Yamada-Okabe, Toshio Matsumoto and Masahiro Abe : Combination with a Defucosylated Anti-HM1.24 Monoclonal Antibody plus Lenalidomide Induces Marked ADCC against Myeloma Cells and Their Progenitors, PLoS ONE, Vol.8, No.12, e83905, 2013.
(Summary)
The immunomodulatory drug lenalidomide (Len) has drawn attention to potentiate antibody-dependent cellular cytotoxicity (ADCC)-mediated immunotherapies. We developed the defucosylated version (YB-AHM) of humanized monoclonal antibody against HM1.24 (CD317) overexpressed in multiple myeloma (MM) cells. In this study, we evaluated ADCC by YB-AHM and Len in combination against MM cells and their progenitors. YB-AHM was able to selectively kill via ADCC MM cells in bone marrow samples from patients with MM with low effector/target ratios, which was further enhanced by treatment with Len. Interestingly, Len also up-regulated HM1.24 expression on MM cells in an effector-dependent manner. HM1.24 was found to be highly expressed in a drug-resistant clonogenic "side population" in MM cells; and this combinatory treatment successfully reduced SP fractions in RPMI 8226 and KMS-11 cells in the presence of effector cells, and suppressed a clonogenic potential of MM cells in colony-forming assays. Collectively, the present study suggests that YB-AHM and Len in combination may become an effective therapeutic strategy in MM, warranting further study to target drug-resistant MM clonogenic cells.
Takeshi Harada, Shuji Ozaki, Asuka Oda, Daisuke Tsuji, Akishige Ikegame, Masami Iwasa, Kengo Udaka, Shiroh Fujii, Shingen Nakamura, Hirokazu Miki, Kumiko Kagawa, Yoshiaki Kuroda, Shigeto Kawai, Kouji Itou, Hisafumi Yamada-Okabe, Toshio Matsumoto and Masahiro Abe : Combination with a defucosylated anti-HM1.24 monoclonal antibody plus lenalidomide induces marked ADCC against myeloma cells and their progenitors., PLoS ONE, Vol.8, No.12, e83905, 2013.
(Summary)
The immunomodulatory drug lenalidomide (Len) has drawn attention to potentiate antibody-dependent cellular cytotoxicity (ADCC)-mediated immunotherapies. We developed the defucosylated version (YB-AHM) of humanized monoclonal antibody against HM1.24 (CD317) overexpressed in multiple myeloma (MM) cells. In this study, we evaluated ADCC by YB-AHM and Len in combination against MM cells and their progenitors. YB-AHM was able to selectively kill via ADCC MM cells in bone marrow samples from patients with MM with low effector/target ratios, which was further enhanced by treatment with Len. Interestingly, Len also up-regulated HM1.24 expression on MM cells in an effector-dependent manner. HM1.24 was found to be highly expressed in a drug-resistant clonogenic "side population" in MM cells; and this combinatory treatment successfully reduced SP fractions in RPMI 8226 and KMS-11 cells in the presence of effector cells, and suppressed a clonogenic potential of MM cells in colony-forming assays. Collectively, the present study suggests that YB-AHM and Len in combination may become an effective therapeutic strategy in MM, warranting further study to target drug-resistant MM clonogenic cells.
Sumiko Yoshida, Ken-ichi Aihara, Yasumasa Ikeda, Yuka Sumitomo-Ueda, Ryoko Uemoto, Kazue Ishikawa, Takayuki Ise, Shusuke Yagi, Takashi Iwase, Yasuhiro Mouri, Matomo Sakari, Takahiro Matsumoto, Ken-ichi Takeyama, Masashi Akaike, Mitsuru Matsumoto, Masataka Sata, Kenneth Walsh, Shigeaki Kato and Toshio Matsumoto : Androgen receptor promotes sex-independent angiogenesis in response to ischemia and is required for activation of vascular endothelial growth factor receptor signaling., Circulation, Vol.128, No.1, 60-71, 2013.
(Summary)
These results document a physiological role of AR in sex-independent angiogenic potency and provide evidence of novel cross-talk between the androgen/AR signaling and VEGF/kinase insert domain protein receptor signaling pathways.
Shingen Nakamura, Hirokazu Miki, Shinsuke Kido, Ayako Nakano, Masahiro Hiasa, Asuka Oda, Hiroe Amou, Keiichiro Watanabe, Takeshi Harada, Shiroh Fujii, Kyoko Takeuchi, Kumiko Kagawa, Shuji Ozaki, Toshio Matsumoto and Masahiro Abe : Activating transcription factor 4, an ER stress mediator, is required for, but exce ssive ER stress suppresses osteoblastogenesis by bortezomib., International Journal of Hematology, Vol.98, No.1, 66-73, 2013.
(Summary)
Endoplasmic reticulum (ER) stress is induced in matrix-producing osteoblasts and plays an essential role in osteoblastogenesis. Although the bone anabolic activity of proteasome inhibitors has been demonstrated, the roles of ER stress induced by proteasome inhibition in osteoblastogenesis remain largely unknown. Here we show that bortezomib translationally increases protein levels of activating transcription factor 4 (ATF4), a downstream mediator of ER stress, in bone marrow stromal cells and MC3T3-E1 preosteoblastic cells. The suppression of ATF4 expression by siRNA abrogated osteocalcin expression and mineralized nodule formation by MC3T3-E1 cells induced by bortezomib, indicating a critical role for ATF4 in bortezomib-mediated osteoblastogenesis. However, bortezomib at 20 nM or higher abolished the mineralized nodule formation along with reductions in the expression of osteoblastogenesis mediators β-catenin and Osterix. Furthermore, at 50 nM, bortezomib induced the expression of C/EBP homologous protein (CHOP), suggesting activation of the ATF4-CHOP pro-apoptotic pathway. These results suggest that a low dose of bortezomib induces osteogenic activity, but that, in contrast, excessive ER stress caused by bortezomib at higher doses hampers osteoblastogenesis. Therefore, dosing schedules for proteasome inhibitors warrant further study to maximize anabolic actions without compromising anti-MM activity in patients with multiple myeloma (MM).
Koichiro Hayashi, Michihiro Nakamura, Hirokazu Miki, Shuji Ozaki, Masahiro Abe, Toshio Matsumoto and Kazunori Ishimura : Gold Nanoparticle Cluster/Plasmon-Enhanced Fluorescent Silica Core-Shell Nanoparticles for X-Ray Computed Tomography/Fluorescence Dual-Mode Imaging of Tumors, Chemical Communications, Vol.49, 5334-5336, 2013.
(Summary)
Owing to the surface plasmon resonance-enhanced electromagnetic field, clustered gold nanoparticles-fluorescent silica core-shell nanoparticles became excited within the therapeutic window and fluoresced strongly in this window. The nanoparticles enabled tumor detection using fluorescence imaging and X-ray computed tomography.
Koichiro Hayashi, Michihiro Nakamura, Wataru Sakamoto, Toshinobu Yogo, Hirokazu Miki, Shuji Ozaki, Masahiro Abe, Toshio Matsumoto and Kazunori Ishimura : "Superparamagnetic Nanoparticle Clusters for Cancer Theranostics Combining Magnetic Resonance Imaging and Hyperthermia Treatment, Theranostics, Vol.3, No.6, 366-376, 2013.
(Summary)
Superparamagnetic nanoparticles (SPIONs) could enable cancer theranostics if magnetic resonance imaging (MRI) and magnetic hyperthermia treatment (MHT) were combined. However, the particle size of SPIONs is smaller than the pores of fenestrated capillaries in normal tissues because superparamagnetism is expressed only at a particle size <10 nm. Therefore, SPIONs leak from the capillaries of normal tissues, resulting in low accumulation in tumors. Furthermore, MHT studies have been conducted in an impractical way: direct injection of magnetic materials into tumor and application of hazardous alternating current (AC) magnetic fields. To accomplish effective enhancement of MRI contrast agents in tumors and inhibition of tumor growth by MHT with intravenous injection and a safe AC magnetic field, we clustered SPIONs not only to prevent their leakage from fenestrated capillaries in normal tissues, but also for increasing their relaxivity and the specific absorption rate. We modified the clusters with folic acid (FA) and polyethylene glycol (PEG) to promote their accumulation in tumors. SPION clustering and cluster modification with FA and PEG were achieved simultaneously via the thiol-ene click reaction. Twenty-four hours after intravenous injection of FA- and PEG-modified SPION nanoclusters (FA-PEG-SPION NCs), they accumulated locally in cancer (not necrotic) tissues within the tumor and enhanced the MRI contrast. Furthermore, 24 h after intravenous injection of the NCs, the mice were placed in an AC magnetic field with H = 8 kA/m and f = 230 kHz (Hf = 1.8×10(9) A/m∙s) for 20 min. The tumors of the mice underwent local heating by application of an AC magnetic field. The temperature of the tumor was higher than the surrounding tissues by ≈6°C at 20 min after treatment. Thirty-five days after treatment, the tumor volume of treated mice was one-tenth that of the control mice. Furthermore, the treated mice were alive after 12 weeks; control mice died up to 8 weeks after treatment.
Shuji Kato, Itsuro Endo, Mitsunori Fujimura, Rika Kuriwaka-Kido, Yuichi Fujinaka, Ken-ichi Aihara, Takashi Iwase, Daisuke Inoue, Masashi Akaike, Masahiro Abe and Toshio Matsumoto : Serum carboxy-terminal telopeptide of type I collagen (ICTP) as a surrogate marker for vulnerable plaques in atherosclerotic patients: A pilot study., Atherosclerosis, Vol.229, No.1, 182-185, 2013.
(Summary)
Evaluation of atherosclerotic plaques depends on invasive intravascular ultrasonography (IVUS). Carboxy-terminal telopeptide of type I collagen (ICTP) is produced by matrix metalloproteinase (MMP)-dependent digestion of type I collagen. Because vulnerable plaques are rich in type I collagen and MMPs from macrophages, we examined the association between serum ICTP and coronary plaques in patients with coronary disease. We recruited 46 men and 17 women without renal failure or bone diseases affecting serum ICTP, who underwent coronary IVUS. Serum ICTP levels were higher in patients with coronary plaques containing more than 10% necrotic core area than in patients with less than 10% necrotic core area. A positive correlation was found between serum ICTP and necrotic core area. Only serum ICTP was positively correlated with necrotic core area by multivariate analysis (p < 0.05). These results suggest that serum ICTP can be used as a non-invasive marker of vulnerable plaques in atherosclerotic patients.
Sumiko Yoshida, Akio Kuroda, 新居 沙央里, 松本 友里, 近藤 絵里, 安藝 菜奈子, Itsuro Endo, Ken-ichi Aihara, 鈴木 麗子, Toshio Matsumoto and Munehide Matsuhisa : The New Paradigm 722 Insulin Pump Can Achieve Good Glycemic Control with Carbohydrate Counting Alone : A Case Report of Type 1 Diabetes Mellitus, Journal of the The Japan Diabetes Society, Vol.56, No.4, 240-245, 2013.
Hiroshi Hagino, Masataka Shiraki, Masao Fukunaga, Tetsuo Nakano, Kunio Takaoka, Yasuo Ohashi, Toshitaka Nakamura and Toshio Matsumoto : Number and severity of prevalent vertebral fractures and the risk of subsequent vertebral fractures in Japanese women with osteoporosis: results from the minodronate trial., Journal of Bone and Mineral Metabolism, Vol.31, No.5, 544-550, 2013.
(Summary)
The aim was to evaluate the risk of new vertebral fractures with the increasing number and severity of prevalent vertebral fractures in women who received placebo or minodronate in a post hoc analysis of a 2-year randomized, double-blind, placebo-controlled study. The subjects were women aged 55-80 years old with 1-5 fragility fractures between the T4 and L4 vertebrae and bone mineral density <80 % of the young adult mean. A total of 704 subjects were randomized to take minodronate 1 mg (n = 359) or placebo (n = 345) once a day for 24 months. In the placebo group, the risk of incident vertebral fractures during the 2-year observational period was significantly related to the number and severity of prevalent vertebral fractures at baseline. The number of prevalent vertebral fractures was an independent risk factor for incident vertebral fracture in multivariate analysis. The relative risk reductions of vertebral fractures by minodronate treatment were 45.2, 61.1, and 64.2 % for patients with 1, 2, and ≥3 prevalent vertebral fractures, respectively, and 87.8, 64.6, and 50.1 % for patients with mild, moderate, and severe prevalent vertebral fractures, respectively. In conclusion, the number of prevalent vertebral fractures is an independent risk factor for incident vertebral fracture and minodronate reduces the fracture risk even in patients at a higher risk for fracture.
(Keyword)
Aged / Aged, 80 and over / Bone Density Conservation Agents / Diphosphonates / Double-Blind Method / Female / Humans / Imidazoles / Middle Aged / Osteoporosis / Spinal Fractures
Rika Kuriwaka-Kido, Shinsuke Kido, Yuka Miyatani, Yuji Ito, Takeshi Kondo, Takashi Omatsu, Bingzi Dong, Itsuro Endo, Ken-ichi Miyamoto and Toshio Matsumoto : Parathyroid hormone (1-34) counteracts the suppression of interleukin-11 expression by glucocorticoid in murine osteoblasts: a possible mechanism for stimulating osteoblast differentiation against glucocorticoid excess., Endocrinology, Vol.154, No.3, 1156-1167, 2013.
(Summary)
Glucocorticoid (GC) excess causes a rapid loss of bone with a reduction in bone formation. Intermittent PTH (1-34) administration stimulates bone formation and counteracts the inhibition of bone formation by GC excess. We have previously demonstrated that mechanical strain enhances interleukin (IL)-11 gene transcription by a rapid induction of FosB expression and protein kinase C (PKC)--mediated phosphorylation of phosphorylated mothers against decapentaplegic (Smad)-1. Because IL-11 suppresses the expression of dickkopf-1 and -2 and stimulates Wnt signaling, IL-11 appears to mediate at least a part of the effect of mechanical strain on osteoblast differentiation and bone formation. The present study was undertaken to examine the effect of PTH(1-34) and GCs on IL-11 expression in murine primary osteoblasts (mPOBs). PTH(1-34) treatment of mPOBs enhanced IL-11 expression in a time- and dose-dependent manner. PTH(1-34) also stimulated FosB expression and Smad1 phosphorylation, which cooperatively stimulated IL-11 gene transcription. PTH(1-34)-induced Smad1 phosphorylation was mediated via PKC and was abrogated in mPOBs from PKC knockout mice. Dexamethasone suppressed IL-11 gene transcription enhanced by PTH(1-34) without affecting FosB expression or Smad1 phosphorylation, and dexamethasone-GC receptor complex was bound to JunD, which forms heterodimers with FosB. High doses of PTH(1-34) counteracted the effect of dexamethasone on apoptosis of mPOBs, which was blunted by neutralizing anti-IL-11 antibody or IL-11 small interfering RNA. These results demonstrate that PTH(1-34) and GCs interact to regulate IL-11 expression in parallel with osteoblast differentiation and apoptosis and suggest that PTH(1-34) and dexamethasone may regulate osteoblast differentiation and apoptosis via their effect on IL-11 expression.
Akio Kuroda, Tetsuyuki Yasuda, Mitsuyoshi Takahara, Fumie Sakamoto, Ryuichi Kasami, Kazuyuki Miyashita, Sumiko Yoshida, Eri Kondo, Ken-ichi Aihara, Itsuro Endo, Taka-Aki Matsuoka, Hideaki Kaneto, Toshio Matsumoto, Iichiro Shimomura and Munehide Matsuhisa : Carbohydrate-to-Insulin Ratio Is Estimated from 300-400 Divided by Total Daily Insulin Dose in Type 1 Diabetes Patients Who Use the Insulin Pump., Diabetes Technology & Therapeutics, Vol.14, No.11, 1077-1080, 2012.
(Summary)
Abstract Background: To optimize insulin dose using insulin pump, basal and bolus insulin doses are widely calculated from total daily insulin dose (TDD). It is recommended that total daily basal insulin dose (TBD) is 50% of TDD and that the carbohydrate-to-insulin ratio (CIR) equals 500 divided by TDD. We recently reported that basal insulin requirement is approximately 30% of TDD. We therefore investigated CIR after adjustment of the proper basal insulin rate. Subjects and Methods: Forty-five Japanese patients with type 1 diabetes were investigated during several weeks of hospitalization. The patients were served standard diabetes meals (25-30 kcal/kg of ideal body weight). Each meal omission was done to confirm basal insulin rate. Target blood glucose level was set at 100 and 150 mg/dL before and 2 h after each meal, respectively. After the basal insulin rate was fixed and target blood glucose levels were achieved, TBD, CIR, TDD, and their products were determined. Results: Mean (±SD) blood glucose levels before and 2 h after meals were 121±47 and 150±61 mg/dL, respectively. TDD was 31.5±9.0 U, and TBD was 27.0±6.5% of TDD. CIR×TDD of breakfast was significantly lower than those of lunch and supper (288±73 vs. 408±92 and 387±83, respectively; P<0.01). Conclusions: CIR has diurnal variance and is estimated from the formula CIR=300/TDD at breakfast or CIR=400/TDD at lunch and supper in type 1 diabetes patients. These results indicate that the insulin dose has been underestimated by using previously established calculations.
Hiroshi Hagino, Toshiyuki Takano, Masao Fukunaga, Masataka Shiraki, Toshitaka Nakamura and Toshio Matsumoto : Eldecalcitol reduces the risk of severe vertebral fractures and improves the health-related quality of life in patients with osteoporosis., Journal of Bone and Mineral Metabolism, Vol.31, No.2, 183-189, 2012.
(Summary)
Eldecalcitol reduces the risk of vertebral fractures in comparison to alfacalcidol in osteoporotic patients under vitamin D repletion. The aim of this study was to evaluate the effects of eldecalcitol on the spinal location of incident vertebral fractures, the severity of the fractures, and the changes in health-related quality of life (HRQOL) compared with those of alfacalcidol. The post hoc analysis has been performed on the data from the three-year, double-blind, randomized, head-to-head clinical trial of eldecalcitol versus alfacalcidol conducted in Japan. A total of 1054 patients were enrolled and randomized to take 0.75 μg eldecalcitol or 1.0 μg alfacalcidol daily for 3 years. The incidence of vertebral fractures was re-evaluated based on the location on the spine (upper T4-T10; lower T11-L4). The severity of vertebral fractures was determined by the semi-quantitative method, and the change in HRQOL was analyzed by using the Medical Outcomes Study Short Form 36-item questionnaire. The incidence of vertebral fracture at the lower spine was less in the eldecalcitol group than in the alfacalcidol group (p = 0.029). The incidence of severe vertebral fracture (Grade 3) was 3.8 % in the eldecalcitol group and 6.7 % in the alfacalcidol group, demonstrated a significant difference between the 2 groups (p = 0.036). Both eldecalcitol and alfacalcidol improved HRQOL in osteoporotic patients. Although no significant differences in each HRQOL scores were observed between eldecalcitol and alfacalcidol during the observational period, overall improvement from baseline of HRQOL scores were clearly observed in the eldecalcitol group. In conclusion, the incidences of lower spinal vertebral fractures and severe vertebral fractures were reduced further by eldecalcitol compared to alfacalcidol in the 3-year clinical trial. Daily treatment with eldecalcitol is effective in improving HRQOL, possibly owing to the reduced risk of lower spinal vertebral fractures and/or severe vertebral fractures.
(Keyword)
Aged / Female / health / Humans / Incidence / Japan / Male / Osteoporosis / Prevalence / quality of life / Risk Factors / Spinal Fractures / vitamin D
Yasumasa Ikeda, Ken-ichi Aihara, Sumiko Yoshida, Takashi Iwase, Soichiro Tajima, Yuki Izawa-Ishizawa, Yoshitaka Kihira, Keisuke Ishizawa, Shuhei Tomita, Koichiro Tsuchiya, Masataka Sata, Masashi Akaike, Shigeaki Kato, Toshio Matsumoto and Toshiaki Tamaki : Heparin cofactor II, a serine protease inhibitor, promotes angiogenesis via activation of the AMP-activated protein kinase-endothelial nitric-oxide synthase signaling pathway, The Journal of Biological Chemistry, Vol.287, No.41, 34256-34263, 2012.
(Summary)
We previously clarified that heparin cofactor II (HCII), a serine proteinase inhibitor, exerts various protective actions on cardiovascular diseases in both experimental and clinical studies. In the present study, we aimed to clarify whether HCII participates in the regulation of angiogenesis. Male heterozygous HCII-deficient (HCII(+/-)) mice and male littermate wild-type (HCII(+/+)) mice at the age of 12-16 weeks were subjected to unilateral hindlimb ligation surgery. Laser speckle blood flow analysis showed that blood flow recovery in response to hindlimb ischemia was delayed in HCII(+/-) mice compared with that in HCII(+/+) mice. Capillary number, arteriole number, and endothelial nitric-oxide synthase (eNOS), AMP-activated protein kinase (AMPK), and liver kinase B1 (LKB1) phosphorylation in ischemic muscles were decreased in HCII(+/-) mice. Human purified HCII (h-HCII) administration almost restored blood flow recovery, capillary density, and arteriole number as well as phosphorylation levels of eNOS, AMPK, and LKB1 in ischemic muscles of HCII(+/-) mice. Although treatment with h-HCII increased phosphorylation levels of eNOS, AMPK, and LKB1 in human aortic endothelial cells (HAECs), the h-HCII-induced eNOS phosphorylation was abolished by compound C, an AMPK inhibitor, and by AMPK siRNA. In a similar fashion, tube formation, proliferation, and migration of HAECs were also promoted by h-HCII treatment and were abrogated by pretreatment with compound C. HCII potentiates the activation of vascular endothelial cells and the promotion of angiogenesis in response to hindlimb ischemia via an AMPK-eNOS signaling pathway. These findings suggest that HCII is a novel therapeutic target for treatment of patients with peripheral circulation insufficiency.
(Keyword)
Heparin cofactor II (HCII) / vascular endothelial cells / angiogenesis
Purpose: Efficient and secure collection of CD34+ cells are crucial for the angiogenic therapies. We have developed autologous peripheral blood-mononuclear cell (MNC) transplantation induced by erythropoietin (rhEPO) for critical ischemic limbs. Methods: Seven patients, including five with arteriosclerosis obliterans, one with Buerger's disease and one with progressive systemic sclerosis, underwent ten cell therapies. The first administration of rhEPO was performed two weeks before apheresis, and the second administration and blood donation were performed one week before apheresis to activate bone marrow. MNCs including CD34+ cells, isolated from peripheral blood by apheresis, were immediately injected intramuscularly into ischemic limbs. Results: The number of peripheral blood-CD34 + cells had significantly increased from 1.32 ± 0.83/microL, before the rhEPO induction, to 1.86 ± 0.94/microL, before the apheresis. The number of transplanted MNCs ranged between 0.5 × 10(9) and 16.5 × 10(9), and that of CD34+ cells, between 0.1 × 10(6) and 12.7 × 10(6), accounting for 0.02%-0.1% of MNCs. There were no serious complications. Finger ulcers with Buerger's disease were significantly improved one month after the transplantations, but the same or other ulcer(s) appeared 2-6 months later. Three patients had an improvement in rest pain, and one patient extended maximum pain-free walking distance. Conclusions: Erythropoietin-induced autologous peripheral blood-MNC transplantation is a useful and safe alternative for ischemic limbs.
Toshio Matsumoto and Itsuro Endo : Eldecalcitol for the treatment of osteoporosis., Drugs of Today, Vol.48, No.3, 189-196, 2012.
(Summary)
Eldecalcitol [1α,25-dihydroxy-2β-(3-hydroxypropyloxy)-vitamin D₃] is an analogue of 1α,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], bearing a hydroxypropyloxy residue at the 2β position. Eldecalcitol shows stronger effects than alfacalcidol to increase bone mineral density and reduce bone resorption markers in osteoporotic patients, and oral once-daily 0.75 μg eldecalcitol reduced vertebral fracture incidence by 26% compared to 1.0 μg alfacalcidol in a 3-year randomized, double-blind, active-comparator clinical trial. The effect of eldecalcitol on vertebral fracture incidence was sustained throughout the 3-year study period, and the annual incidence of vertebral fracture during the third year was significantly lower with eldecalcitol rather than with alfacalcidol treatment (3.9% vs 7.0%, respectively). Eldecalcitol also reduced the incidence of wrist fractures by 71% compared to alfacalcidol. Eldecalcitol is well tolerated and is not associated with serious side effects including sustained hypercalcemia. Eldecalcitol was approved for the treatment of osteoporosis in Japan in 2011.
(Keyword)
Adult / Aged / Animals / Bone Density / Bone Density Conservation Agents / Clinical Trials as Topic / Clinical Trials, Phase I as Topic / Clinical Trials, Phase II as Topic / Drug Evaluation, Preclinical / Drug Interactions / Female / Fractures, Bone / Humans / Middle Aged / Osteoporosis / Osteoporosis, Postmenopausal / Randomized Controlled Trials as Topic / Rats / Vitamin D
Kumiko Kagawa, Ayako Nakano, Hirokazu Miki, Asuka Oda, Hiroe Amou, Kyoko Takeuchi, Shingen Nakamura, Takeshi Harada, Shiro Fujii, Kenichiro Yata, Shuji Ozaki, Toshio Matsumoto and Masahiro Abe : Inhibition of TACE activity enhances the susceptibility of myeloma cells to TRAIL., PLoS ONE, Vol.7, No.2, 2012.
(Summary)
These results demonstrate that MM cells post-translationally down-modulate the cell surface expression of DR4 through ectodomain shedding by endogenous TACE, and that TACE inhibition is able to restore cell surface DR4 levels and the susceptibility of MM cells to TRAIL or an agonistic antibody against DR4. Thus, TACE may protect MM cells from TRAIL-mediated death through down-modulation of cell-surface DR4. It can be envisaged that TACE inhibition augments clinical efficacy of TRAIL-based immunotherapy against MM, which eventually becomes resistant to the present therapeutic modalities.
Hirotsugu Kurobe, Ken-ichi Aihara, Higashida Mayuko, Hirata Yoichiro, Nishiya Masako, Matsuoka Yuki, Tamotsu Kanbara, Nakayama Taisuke, Hajime Kinoshita, Mikio Sugano, Eiki Fujimoto, Kurobe Ayako, Sugawara Noriko, Takashi Kitaichi, Masashi Akaike, Masataka Sata, Toshio Matsumoto and Tetsuya Kitagawa : Ezetimibe monotherapy ameliorates vascular function in patients with hypercholesterolemia through decreasing oxidative stress., Journal of Atherosclerosis and Thrombosis, Vol.18, No.12, 1080-1089, 2011.
(Summary)
Ezetimibe, an inhibitor of cholesterol intestinal absorption, is a lipid lowering agent. However, anti-atherogenic effects of ezetimibe have not been fully elucidated. Therefore, the objective in this study was to clarify the vascular protective effects of ezetimibe in patients with hypercholesterolemia. Ezetimibe was administered to 20 patients with hypercholesterolemia (group E), and 20 age- and sex-matched patients with hypercholesterolemia were followed as controls (group C). Difference in metabolic profiles and cardiovascular surrogate markers before ezetimibe treatment and after 12 weeks of ezetimibe treatment were statistically evaluated. Ezetimibe treatment significantly reduced serum levels of low-density lipoprotein cholesterol (LDL-C) and malondialdehyde-modified low-density lipoprotein (MDA-LDL). In addition, the values of body mass index, body weight, waist circumference, plasma HbA1c and urinary albumin were significantly decreased in group E compared to those in group C. On the other hand, high-density lipoprotein cholesterol (HDL-C) and adiponectin levels were significantly increased in group E compared to those in group C. The values of brachial-ankle pulse wave velocity (ba-PWV), mean arterial blood pressure (m-ABP), and % of flow-mediated dilation (FMD) were significantly improved in group E. Furthermore, ultrasonic studies demonstrated amelioration of the vascular stiffness of common carotid arteries in group E but not in group C. These vascular protective effects of ezetimibe were statistically correlated with the decreased values of MDA-LDL and MDA-LDL-to-LDL-C ratio but not with those of LDL-C. Ezetimibe has a lipid lowering-independent vascular protective effect in patients with hypercholesterolemia through decreasing oxidative stress.
Hirokazu Miki, Shingen Nakamura, Shuji Ozaki, A Oda, H Amou, Akishige Ikegame, Keiichiro Watanabe, Masahiro Hiasa, Q Cui, T Harada, Shiroh Fujii, A Nakano, Kumiko Kagawa, Kyoko Takeuchi, Ken-ichiro Yata, A Sakai, Masahiro Abe and Toshio Matsumoto : KRN5500, a spicamycin derivative, exerts anti-myeloma effects through impairing both myeloma cells and osteoclasts., British Journal of Haematology, Vol.155, No.3, 328-339, 2011.
(Summary)
The spicamycin analogue KRN5500 alters glycoprotein processing and induces damage in the endoplasmic reticulum (ER)-Golgi apparatus in cancer cells. In the present study, we explored the cytotoxic effects of KRN5500 on multiple myeloma (MM) cells and the bone marrow microenvironment with special reference to ER stress. Cell proliferation assay showed that KRN5500 induced G1 arrest and apoptosis in MM cells in a time- and dose-dependent manner. KRN5500 enhanced ER stress independently of caspase activation in MM cells. This cell death was observed even in the presence of bone marrow stroma cells or osteoclasts. Notably, KRN5500 induced cell death also in osteoclasts. In vivo effects of KRN5500 were evaluated using two xenograft models established in severe combined immunodeficient (SCID) mice by either subcutaneous injection of RPMI 8226 cells or intra-bone injection of INA-6 cells to subcutaneously implanted rabbit bones (SCID-rab model). KRN5500 significantly inhibited tumour growth in both animal models, and decreased the number of osteoclasts, which resulted in prevention of bone destruction in the SCID-rab model. These results suggest that KRN5500 exerts anti-MM effects through impairing both MM cells and osteoclasts. Therefore, this unique mechanism of KRN5500 might be a useful therapeutic option in patients with MM.
Toshio Matsumoto, Rika Kuriwaka-Kido, Takeshi Kondo, Itsuro Endo and Shinsuke Kido : Regulation of osteoblast differentiation by interleukin-11 via AP-1 and Smad signaling., Endocrine Journal, Vol.59, No.2, 91-101, 2011.
(Summary)
Mechanical stress and parathyroid hormone (PTH) are major stimulators, and aging and glucocorticoids excess are important suppressors of osteoblast differentiation. Mechanical stress and PTH stimulate interleukin (IL)-11 expression in cells of osteoblast lineage by enhancing transcription of IL-11 gene via an increase in intracellular Ca² . The elevated Ca² activates extracellular signal-regulated kinase (ERK) to enhance phosphorylation of cyclic AMP response element-binding protein (CREB), which binds to the fosB gene promoter and enhances FosB expression. FosB dimerizes with JunD on the IL-11 gene promoter to enhance its transcription. Both mechanical stress and PTH also stimulate phosphorylation of Smad1 via an activation of protein kinase C (PKC). Phosphorylated Smad1 binds to the IL-11 gene promoter and forms complex with FosB/JunD to further enhance IL-11 gene transcription. The increased IL-11 then suppresses expression of Wnt inhibitors, including Dickkopf 1 (Dkk1) and 2, and enhances Wnt signaling to stimulate osteoblast differentiation and inhibit adipocyte differentiation. The suppression of osteoblast differentiation by aging involves a decrease in IL-11 gene transcription by a reduction in JunD binding to the activator protein (AP)-1 site of the IL-11 gene promoter. Glucocorticoids inhibit transcriptional activation of IL-11 gene by an interaction of glucocorticoid-glucocorticoid receptor (GR) complex with FosB/JunD heterodimer. Thus, factors that enhance osteoblast differentiation stimulate, and those which suppress osteoblast differentiation inhibit IL-11 gene transcription, and IL-11 enhances Wnt signaling by suppressing expression of its inhibitors. These observations are consistent with the notion that IL-11 mediates stimulatory and inhibitory signals of osteoblast differentiation by affecting Wnt signaling.
Toshio Matsumoto, Masako Ito, Yasufumi Hayashi, Takako Hirota, Yusuke Tanigawara, Teruki Sone, Masao Fukunaga, Masataka Shiraki and Toshitaka Nakamura : A new active vitamin D3 analog, eldecalcitol, prevents the risk of osteoporotic fractures--a randomized, active comparator, double-blind study., Bone, Vol.49, No.4, 605-612, 2011.
(Summary)
Eldecalcitol is an analog of 1,25-dihydroxyvitamin D(3) that improves bone mineral density; however, the effect of eldecalcitol on the risk of fractures is unclear. The objective of this study is to examine whether eldecalcitol is superior to alfacalcidol in preventing osteoporotic fractures. This trial is registered with ClinicalTrials.gov, number NCT00144456. This 3 year randomized, double-blind, active comparator, superiority trial tested the efficacy of daily oral 0.75 g eldecalcitol versus 1.0 g alfacalcidol for prevention of osteoporotic fractures. 1054 osteoporotic patients 46 to 92 years old were randomly assigned 1:1 to receive eldecalcitol (n=528) or alfacalcidol (n=526). Patients were stratified by study site and serum 25-hydroxyvitamin D level. Patients with low serum 25-hydroxyvitamin D levels (<50 nmol/L) were supplemented with 400 IU/day vitamin D(3). Primary end point was incident vertebral fractures. Secondary end points included any non-vertebral fractures and change in bone mineral density and bone turnover markers. Compared with the alfacalcidol group, the incidence of vertebral fractures was lower in eldecalcitol group after 36 months of treatment (13.4 vs. 17.5%; hazard ratio, 0.74; predefined 90% confidence interval [CI], 0.56-0.97). Eldecalcitol reduced turnover markers and increased bone mineral density more strongly than alfacalcidol. Eldecalcitol reduced the incidence of three major non-vertebral fractures, which was due to a marked reduction in wrist fractures by a post-hoc analysis (1.1 vs. 3.6%; hazard ratio, 0.29; 95% CI, 0.11-0.77). Among the adverse events, the incidence of increase in serum and urinary calcium was higher in the eldecalcitol group, without any difference in glomerular filtration rate between the two groups. Eldecalcitol is more efficacious than alfacalcidol in preventing vertebral and wrist fractures in osteoporotic patients with vitamin D sufficiency, with a safety profile similar to alfacalcidol.
(Keyword)
Aged / Aged, 80 and over / Bone Density / Bone Remodeling / Cholecalciferol / Double-Blind Method / Female / Hormones / Humans / Incidence / Japan / Kaplan-Meier Estimate / Male / Middle Aged / Osteoporotic Fractures / Risk Factors / Spinal Fractures / Treatment Outcome / vitamin D
Multiple myeloma (MM) cells stimulate osteoclastogenesis, and osteoclasts (OCs) in turn enhance MM growth and drug resistance, resulting in a vicious cycle. V9V2 T cells exert potent anti-tumor effects, making T cell-based immunotherapies using these cells attractive candidates for currently incurable malignancies, such as MM. However, the impact of such treatments on the MM-OC interaction is largely unknown. We demonstrate here that V9V2 T cells expanded by zoledronic acid and IL-2 exerted potent cytotoxic effects on both MM cells and OCs, even in coculture settings, but showed no such effect on bone marrow stromal cells. V9V2 T cells marginally affected colony formation from normal hematopoietic progenitors, and furthermore migrated toward osteopontin and MIP-1, factors produced by the MM-OC interaction. These results suggest that V9V2 T cells expanded by zoledronic acid and IL-2 are able to migrate to MM bone lesions and preferentially target OCs as well as MM cells, thereby inhibiting both tumor expansion and bone destruction.
Ayako Nakano, Masahiro Abe, Asuka Oda, Hiroe Amou, Masahiro Hiasa, Shingen Nakamura, Hirokazu Miki, Takeshi Harada, Shirou Fujii, Kumiko Kagawa, Kyoko Takeuchi, Takashi Watanabe, Shuji Ozaki and Toshio Matsumoto : Delayed treatment with vitamin C and N-acetyl-L: -cysteine protects Schwann cells without compromising the anti-myeloma activity of bortezomib., International Journal of Hematology, Vol.93, No.6, 727-735, 2011.
(Summary)
Bortezomib-induced peripheral neuropathy (BIPN) emerges as a disabling adverse effect. As rat models for BIPN have demonstrated damage in nerve Schwann cells, we screened for cytoprotective agents to devise a method of rescuing Schwann cells from the cytotoxic effects of bortezomib without compromising its anti-myeloma effects. Schwann cells underwent macroautophagy along with cytoplasmic inclusion body and vacuole formation, and appeared much less susceptible to bortezomib-induced cytotoxicity than did myeloma cells. Vitamin C or N-acetyl-L: -cysteine (NAC) achieved near-complete rescue of Schwann cells treated with bortezomib at 30 nM or less, and these agents in combination are able to cooperatively inhibit the morphological changes and the cytotoxicity in Schwann cells with higher doses of bortezomib. The delayed addition of vitamin C and/or NAC after the exposure to bortezomib alleviated the cytotoxicity in Schwann cells but not myeloma cells. These results suggest that delayed treatment with these agents may be instrumental in prophylaxis of BIPN.
J Asano, A Nakano, A Oda, H Amou, Masahiro Hiasa, Kyoko Takeuchi, H Miki, S Nakamura, T Harada, Shiroh Fujii, Kumiko Kagawa, Itsuro Endo, Ken-ichiro Yata, A Sakai, Shuji Ozaki, Toshio Matsumoto and Masahiro Abe : The serine/threonine kinase Pim-2 is a novel anti-apoptotic mediator in myeloma cells., Leukemia, 2011.
(Summary)
Bone marrow stromal cells (BMSCs) and osteoclasts (OCs) confer multiple myeloma (MM) cell survival through elaborating factors. We demonstrate herein that IL-6 and TNF family cytokines, TNF, BAFF and APRIL, but not IGF-1 cooperatively enhance the expression of the serine/threonine kinase Pim-2 in MM cells. BMSCs and OCs upregulate Pim-2 expression in MM cells largely via the IL-6/STAT3 and NF-B pathway, respectively. Pim-2 short interfering RNA reduces MM cell viability in cocultures with BMSCs or OCs. Thus, upregulation of Pim-2 appears to be a novel anti-apoptotic mechanism for MM cell survival. Interestingly, the mammalian target of rapamycin inhibitor rapamycin further suppresses the MM cell viability in combination with the Pim-2 silencing. The Pim inhibitor (Z)-5-(4-propoxybenzylidene) thiazolidine-2, 4-dione and the PI3K inhibitor LY294002 cooperatively enhance MM cell death. The Pim inhibitor suppresses 4E-BP1 phosphorylation along with the reduction of Mcl-1 and c-Myc. Pim-2 may therefore become a new target for MM treatment.Leukemia advance online publication, 8 April 2011; doi:10.1038/leu.2011.60.
Shusuke Yagi, Masashi Akaike, Ken-ichi Aihara, Takashi Iwase, Kazue Ishikawa, Sumiko Yoshida, Yuka Sumitomo-Ueda, Kenya Kusunose, Toshiyuki Niki, Koji Yamaguchi, Kunihiko Koshiba, Yoshio Taketani, Noriko Tomita, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Toshio Matsumoto and Masataka Sata : Effect of low-dose (1 mg/day) pitavastatin on left ventricular diastolic function and albuminuria in patients with hyperlipidemia., The American Journal of Cardiology, Vol.107, No.11, 1644-1649, 2011.
(Summary)
The aim of the present study was to evaluate the factors that modulate the protective action of statins on cardiorenal function, regardless of the lipid-lowering effect. To treat abnormal serum lipid profiles, low-dose pitavastatin (1.0 mg/day) was administered to 65 hyperlipidemic patients. The exclusion criteria included left ventricular ejection fraction <40% and apparent renal disease. Age- and gender-matched patients with hyperlipidemia (n = 40) served as the controls. After 12 to 16 weeks of pitavastatin treatment, pitavastatin had decreased low-density lipoprotein cholesterol (from 143.5 ± 31.4 to 98.2 ± 19.4 mg/dl, p <0.01), triglycerides (from 157.7 ± 57.2 to 140.5 ± 60.7 mg/dl, p <0.01), E/e' (from 10.8 ± 6.2 to 9.0 ± 4.5, p <0.05), a parameter of left ventricular diastolic function, and albuminuria (from 47.6 ± 55.9 to 28.5 ± 40.0 mg/g creatinine, p <0.01). Furthermore, pitavastatin decreased serum transforming growth factor-1 (from 709 ± 242 to 550 ± 299 pg/ml, p <0.01), urinary 8-hydroxy-2'-deoxyguanosine (from 6.6 ± 4.1 to 5.0 ± 3.1 g/g creatinine, p <0.01), an oxidative stress marker, and increased urinary nitrate and nitrite (from 22.5 ± 14.6 to 29.4 ± 27.6 nmol/g creatinine, p <0.05). No such changes were observed in the controls. Multiple regression analysis in the pitavastatin group revealed the effect of pitavastatin on cardiorenal function was associated with suppression of oxidative stress, but not on low-density lipoprotein cholesterol reduction. In conclusion, pitavastatin decreases E/e' and albuminuria, which is associated with suppression of oxidative stress.
Michihiro Nakamura, Shuji Ozaki, Masahiro Abe, Toshio Matsumoto and Kazunori Ishimura : One-pot synthesis and characterization of dual fluorescent thiol-organosilica nanoparticles as non-photoblinking quantum dots and their applications for biological imaging, Journal of Materials Chemistry, Vol.21, 4689-4695, 2011.
Shunji Hashizume, Masashi Akaike, Hiroyuki Azuma, Kazue Ishikawa, Sumiko Yoshida, Yuka Ueda, Shusuke Yagi, Yasumasa Ikeda, Takashi Iwase, Ken-ichi Aihara, Masahiro Abe, Masataka Sata and Toshio Matsumoto : Activation of peroxisome proliferator-activated receptor α in megakaryocytes reduces platelet-derived growth factor-BB in platelets., Journal of Atherosclerosis and Thrombosis, Vol.18, No.2, 138-147, 2011.
(Summary)
Platelet-derived growth factor (PDGF)-BB plays a crucial role in atherosclerosis and vascular remodeling by promoting the migration and proliferation of vascular smooth muscle cells. The objective of this study was to clarify the pleiotropic effect of peroxisome proliferator-activated receptor α (PPARα) activators on PDGF-BB expression in megakaryocytes and platelets. The expression of PPARα in a human erythroleukemia (HEL) cells was clearly detected by reverse transcriptase-PCR and immunofluorescence microscopy. The expression level of PPARα in HEL cells was unchanged regardless of differentiation into megakaryocytic cells by treatment with phorbol 12-myristate 13 acetate (TPA). The TPA-induced expression of PDGF-B mRNA and PDGF-BB protein levels in culture media was significantly decreased by treatment with PPARα activators, Wy14643 and fenofibric acid, in a dose-dependent manner. PDGF-BB expression induced by inflammatory cytokines, including interleukin-1β or interleukin-6, was also significantly suppressed by treatment with PPARα activators. Immunohistochemistry of human bone marrow showed the expression of PPARα in both the nucleus and cytoplasm of megakaryocytes. In addition, PDGF-BB levels in platelets were significantly decreased from 1,800±870 to 1,470±840 pg/10(5) platelets (mean±SD, p<0.05) by treatment with 300 mg fenofibrate once daily for 4 weeks in 13 patients with dyslipidemia. Activation of PPARα in megakaryocytes reduces PDGF-BB expression in platelets. PPARα activators may exert vasculo-protective action through suppression of PDGF-BB production in a megakaryocyte/platelet pathway.
Takayuki Ise, Ken-ichi Aihara, Yuka Ueda, Sumiko Yoshida, Yasumasa Ikeda, Shusuke Yagi, Takashi Iwase, Hirotsugu Yamada, Masashi Akaike, Masataka Sata and Toshio Matsumoto : Plasma heparin cofactor II activity is inversely associated with left atrial volume and diastolic dysfunction in humans with cardiovascular risk factors., Hypertension Research, Vol.34, No.2, 225-231, 2010.
(Summary)
Thrombin has a crucial role in cardiac remodeling through protease-activated receptor-1 activation in cardiac fibroblasts and cardiomyocytes. As heparin cofactor II (HCII) inhibits the action of tissue thrombin in the cardiovascular system, it is possible that HCII counteracts the development of cardiac remodeling. We investigated the relationships between plasma HCII activity and surrogate markers of cardiac geometry, including left atrial volume index (LAVI), relative wall thickness (RWT) and left ventricular mass index, and deceleration time (DcT) and the ratio of peak E velocity to early diastolic mitral annulus velocity (E/e' ratio) as surrogate markers of left ventricular diastolic dysfunction measured using echocardiography in 304 Japanese elderly individuals without systolic heart failure (169 men and 135 women; mean age: 65.4 ± 11.8 years). Mean plasma HCII activity in all participants was 95.8 ± 17.0% and there was no difference between the mean plasma HCII activities in males and females. Multiple regression analysis revealed that there were significant inverse relationships between plasma HCII activity and LAVI (coefficient: -0.2302, P<0.001), between HCII activity and RWT (coefficient: -0.0007, P<0.05), between HCII activity and DcT (coefficient: -0.5189, P<0.05) and between HCII activity and E/e' ratio (coefficient: -0.0558, P<0.01). Plasma HCII activity was independently and inversely associated with the development of cardiac remodeling, including cardiac concentric change, left atrial enlargement and left ventricular diastolic dysfunction. These findings suggest that cardiac tissue thrombin inactivation by HCII is a novel therapeutic target for cardiac remodeling and atherosclerosis.
Pulmonary arterial hypertension (PAH) is a frequent complication in patients with systemic sclerosis. Bosentan is used in patients with symptomatic PAH; however, it has not been established whether or not bosentan ameliorates the progression of PAH in patients with no PAH-related symptoms. We present a case of systemic sclerosis with no PAH-related symptoms in which bosentan ameliorated exercise-induced PAH evaluated by 6-minute walk stress echocardiography, brachial flow-mediated dilation, and skin temperature of hands and feet. The results suggest that administration of bosentan in patients with early-stage PAH ameliorates pulmonary arterial vasodilatation through improvement of endothelial function.
Shinsuke Kido, Rika Kuriwaka-Kido, Yuka Umino-Miyatani, Itsuro Endo, Daisuke Inoue, Hisaaki Taniguchi, Yasumichi Inoue, Takeshi Imamura and Toshio Matsumoto : Mechanical stress activates Smad pathway through PKCδ to enhance interleukin-11 gene transcription in osteoblasts., PLoS ONE, Vol.5, No.9, 2010.
(Summary)
These results demonstrate that PKCδ-BR-Smads pathway plays an important role in the intracellular signaling in response to mechanical stress, and that a cross-talk between PKCδ-BR-Smads and ΔFosB/JunD pathways synergistically stimulates IL-11 gene transcription in response to mechanical stress.
(Keyword)
Animals / Bone Morphogenetic Proteins / Cell Line / Cells, Cultured / Humans / Interleukin-11 / Mice / Osteoblasts / Phosphorylation / Protein Binding / Protein Kinase C-delta / Signal Transduction / Smad Proteins / Stress, Mechanical / Transcription, Genetic
Shusuke Yagi, Masashi Akaike, Ken-ichi Aihara, Takashi Iwase, Sumiko Yoshida, Yuka Ueda, Yasumasa Ikeda, Kazue Ishikawa, Toshio Matsumoto and Masataka Sata : High plasma aldosterone concentration is a novel risk factor of cognitive impairment in patients with hypertension., Hypertension Research, Vol.34, No.1, 74-78, 2010.
(Summary)
Cognitive impairment leading to dementia is associated with high prevalence of hypertension, decreased quality of life and poor prognosis. Aldosterone is known as a risk factor for cardiovascular and cerebrovascular diseases. In addition, mineral corticoid receptors are abundantly expressed in the hippocampus, which plays a pivotal role in cognitive function; however, it has not been determined whether plasma aldosterone level is associated with cognitive impairment in patients with hypertension. We enrolled 68 patients with essential hypertension and assessed their cardiovascular risk factors, including blood pressure, hyperlipidemia, diabetes mellitus, obesity, smoking, history of cerebral infarction, renal function, parameters of inflammation, oxidative stress and nitric oxide bioavailability, a parameter of cerebral blood flow and carotid plaque by ultrasound examination, plasma renin activity and plasma aldosterone concentration (PAC). The mini-mental state examination (MMSE) was used to evaluate cognitive function. The relevance of cardiovascular risk factors and MMSE score was statistically evaluated. Multiple regression analysis showed that age (P<0.01), PAC (P<0.01) and history of cerebral infarction (P<0.05) were inversely and independently associated with MMSE score. Mineral corticoid receptor antagonists, including spironolactone and eplerenone, increased MMSE score in seven patients with hypertension, but not in the controls. In conclusion, increased PAC is associated with impaired cognitive function and mineral corticoid receptor blockade may protect against not only cardiovascular mortality, but also cognitive impairment in patients with hypertension.Hypertension Research advance online publication, 23 September 2010; doi:10.1038/hr.2010.179.
Takako Taniguchi, Shinsuke Kido, Emiko Yamauchi, Masahiro Abe, Toshio Matsumoto and Hisaaki Taniguchi : Induction of endosomal/lysosomal pathways in differentiating osteoblasts as revealed by combined proteomic and transcriptomic analyses., FEBS Letters, Vol.584, No.18, 3969-3974, 2010.
(Summary)
We have analyzed proteome changes associated with bone-forming osteoblast differentiation by quantitative differential proteomic and transcriptomic analyses using in vitro differentiation model. Sixty nine proteins were found up-regulated (>2-fold) and 18 were down-regulated (<0.5-fold) at protein level. The mRNA levels of these proteins were then analyzed by quantitative real-time PCR combined with clustering analysis. The most prominent cluster with increased protein and mRNA levels contains endosomal and lysosomal proteins, demonstrating the drastic induction of degradative endosomal/lysosomal pathways in osteoblasts. Osteoblasts, therefore, are involved not only in the synthesis but also in the turnover of the extracellular matrix proteins such as collagens.
Yuka Sumitomo-Ueda, Ken-ichi Aihara, Takayuki Ise, Sumiko Yoshida, Yasumasa Ikeda, Ryoko Uemoto, Shusuke Yagi, Takashi Iwase, Kazue Ishikawa, Yoichiro Hirata, Masashi Akaike, Masataka Sata, Shigeaki Kato and Toshio Matsumoto : Heparin cofactor II protects against angiotensin II-induced cardiac remodeling via attenuation of oxidative stress in mice., Hypertension, Vol.56, No.3, 430-436, 2010.
(Summary)
Heparin cofactor II (HCII), a serine protease inhibitor, inhibits tissue thrombin action after binding with dermatan sulfate proteoglycans in the extracellular matrix of the vascular system. We previously reported that heterozygous HCII-deficient (HCII(+/-)) humans and mice demonstrate acceleration of vascular remodeling, including atherosclerosis. However, the action of HCII on cardiac remodeling never has been determined. HCII(+/+) and HCII(+/-) mice at age 25 weeks were infused with angiotensin II (Ang II; 2.0 mg/kg/d) for 2 weeks by an osmotic mini-pump. Echocardiography revealed acceleration of cardiac concentric remodeling in HCII(+/-) mice and larger left atrial volume in HCII(+/-) mice than in HCII(+/+) mice. Histopathologic studies showed more prominent interstitial fibrosis in both the left atrium and left ventricle in HCII(+/-) mice than in HCII(+/+) mice. Daily urinary excretion of 8-hydroxy-2'-deoxyguanosine, a parameter of oxidative stress, and dihydroethidium-positive spots, indicating superoxide production in the myocardium, were markedly increased in Ang II-treated HCII(+/-) mice compared to those in HCII(+/+) mice. Cardiac gene expression levels of atrial natriuretic peptides and brain natriuretic peptides, members of the natriuretic peptide family, Nox 4, Rac-1, and p67(phox) as components of NAD(P)H oxidase, and transforming growth factor-beta1 and procollagen III were more augmented in HCII(+/-) mice than in HCII(+/+) mice. However, administration of human HCII protein attenuated all of those abnormalities in Ang II-treated HCII(+/-) mice. Moreover, human HCII protein supplementation almost abolished cardiac fibrosis in Ang II-treated HCII(+/+) mice. The results indicate that HCII has a protective role against Ang II-induced cardiac remodeling through suppression of the NAD(P)H oxidase-transforming growth factor-beta1 pathway.
Ryo Okazaki, Toshitsugu Sugimoto, Hiroshi Kaji, Yoshio Fujii, Masataka Shiraki, Daisuke Inoue, Itsuro Endo, Toshio Okano, Takako Hirota, Issei Kurahashi and Toshio Matsumoto : Vitamin D insufficiency defined by serum 25-hydroxyvitamin D and parathyroid hormone before and after oral vitamin D3 load in Japanese subjects., Journal of Bone and Mineral Metabolism, Vol.29, No.1, 103-110, 2010.
(Summary)
Vitamin D insufficiency is a risk for both skeletal and nonskeletal health. However, some ambiguity remains about threshold serum 25(OH)D for vitamin D insufficiency. To determine the threshold serum 25(OH)D to maintain normal calcium availability without elevation in serum parathyroid hormone (PTH) among Japanese subjects with various calcium intakes, we conducted a multicenter prospective open-labeled study. We recruited 107 ambulatory subjects without disorders affecting vitamin D metabolism to whom oral vitamin D₃ 800 IU/day for 4 weeks or 1,200 IU/day for 8 weeks was given. Serum 25(OH)D, PTH, calcium, phosphate, and magnesium were measured before and after vitamin D₃ supplementation. Calcium intake was assessed by questionnaires. When all the data were combined, serum 25(OH)D was negatively correlated with PTH. The cubic spline curve between serum 25(OH)D and PTH indicated PTH reached its plateau between 35 and 40 pg/ml at 25(OH)D between 25 and 30 ng/ml. Vitamin D₃ supplementation increased serum 25(OH)D and decreased PTH. Change in PTH correlated positively with baseline serum 25(OH)D. From the regression analyses, baseline serum 25(OH)D above 28 ng/ml corresponded to the threshold level without reduction in PTH after vitamin D₃ supplementation. In multivariate regression analyses, age but not calcium intake was a significant determinant of PTH. We concluded that a serum 25(OH)D level of 28 ng/ml was identified as a threshold for vitamin D insufficiency necessary to stabilize PTH to optimal levels.
(Keyword)
Adult / Aged / Aged, 80 and over / Cholecalciferol / Female / Humans / Male / Middle Aged / Osteoporosis / Parathyroid Hormone / Prospective Studies / Vitamin D / Vitamin D Deficiency
Sumiko Yoshida, Ken-ichi Aihara, Hiroyuki Azuma, Ryoko Uemoto, Yuka Sumitomo-Ueda, Shusuke Yagi, Yasumasa Ikeda, Takashi Iwase, Susumu Nishio, Hiromi Kawano, Junko Miki, Hirotsugu Yamada, Yoichiro Hirata, Masashi Akaike, Masataka Sata and Toshio Matsumoto : Dehydroepiandrosterone sulfate is inversely associated with sex-dependent diverse carotid atherosclerosis regardless of endothelial function., Atherosclerosis, Vol.212, No.1, 310-315, 2010.
(Summary)
BACKGROUND: Dehydroepiandrosterone sulfate (DHEAS) is thought to be associated with life expectancy and anti-aging. However, its biological significance in atherosclerosis remains controversial. Therefore, the aim of this study was to determine whether DHEAS is associated with development of carotid atherosclerosis in subjects with cardiovascular risk factors. SUBJECTS AND METHODS: A total of 419 Japanese individuals (208 males and 211 females) were recruited from Tokushima University Hospital, Japan. In all subjects, maximum intima-media thickness (max-IMT) in all carotid arteries, and mean-IMT and mean blood flow volume (BFV) in the common carotid arteries (CCA) were measured by ultrasonography; endothelial function was assessed by flow-mediated vasodilation of the brachial artery (%FMD). Serum DHEAS and classical cardiovascular risk factors were also evaluated. Statistical significance was determined by multiple regression analysis to elucidate independent determinants of max-IMT, mean-IMT, mean CCA-BFV, and %FMD. RESULTS: Serum DHEAS levels were higher in males than in females. Multiple regression analysis revealed that DHEAS was an independent negative factor for both max-IMT and mean-IMT in males but not in females. In contrast, DHEAS was the sole positive factor for mean CCA-BFV in females but not in males. In addition, there was no significant relationship between %FMD and DHEAS regardless of sex and other confounding factors. CONCLUSION: Although DHEAS is not involved in endothelial function, DHEAS is inversely associated with sex-dependent diverse carotid atherosclerosis such as increased max-IMT and mean-IMT in males and decreased CCA-BFV in females.
Doxorubicin (Dox) has been used as a potent anticancer agent, but serious cardiotoxicity precludes its use in a wide range of patients. We have reported that the androgen-androgen receptor (AR) system plays important roles in cardiac growth and protection from angiotensin II-induced cardiac remodeling. The present study was undertaken to clarify whether the androgen-AR system exerts a cardioprotective effect against Dox-induced cardiotoxicity. Male AR knockout (ARKO) and age-matched littermate male wild-type (WT) mice at 25 wk of age were given ip injections of Dox (20 mg/kg) or a vehicle. The survival rate and left ventricular function in Dox-treated male ARKO mice were reduced compared with those in Dox-treated male WT mice. Electron microscopic study showed prominent vacuole formation of myocardial mitochondria in Dox-treated male ARKO mice. Cardiac oxidative stress and apoptosis of cardiomyocytes were increased more prominently by Dox treatment in male ARKO mice than in male WT mice. In addition, Dox-induced reduction in the expression of cardiac mitochondria transcription factor A (Tfam) and phosphorylation of serine-threonine kinase (Akt) was more pronounced in male ARKO mice than in male WT mice. In cardiac myoblast cells, testosterone up-regulated Akt phosphorylation and Tfam expression and exerted an antiapoptotic effect against Dox-induced cardiotoxicity. Collectively, the results demonstrate that Dox-induced cardiotoxicity is aggravated in male ARKO mice via exacerbation of mitochondrial damage and superoxide generation, leading to enhanced apoptosis of cardiomyocytes. Thus, the androgen-AR system is thought to counteract Dox-induced cardiotoxicity partly through activation of the Akt pathway and up-regulation of Tfam to protect cardiomyocytes from mitochondrial damage and apoptosis.
(Keyword)
Androgens / Animals / Antineoplastic Agents / Apoptosis / Blotting, Western / Cell Line / Cell Survival / DNA-Binding Proteins / Doxorubicin / Echocardiography / High Mobility Group Proteins / Immunoprecipitation / In Situ Nick-End Labeling / Male / Mice / Mice, Knockout / Microscopy, Electron / Myocardium / Myocytes, Cardiac / Oxidative Stress / Phosphorylation / Protein-Serine-Threonine Kinases / Rats / Receptors, Androgen / Superoxides / Testosterone / Thiobarbituric Acid Reactive Substances / Ventricular Function, Left
Shusuke Yagi, Masashi Akaike, Mitsunori Fujimura, Takehiko Kimura, Takeshi Nishiuchi, Takashi Iwase, Ken-ichi Aihara, Sumiko Yoshida, Yuka Sumitomo-Ueda, Kenya Kusunose, Toshiyuki Niki, Koji Yamaguchi, Kunihiko Koshiba, Yoichiro Hirata, Munkhbaatar Dagvasumberel, Yoshio Taketani, Noriko Tomita, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Toshio Matsumoto and Masataka Sata : Congenital ventricular aneurysm as an unexpected complication of monomorphic premature ventricular contractions., Internal Medicine, Vol.49, No.10, 907-912, 2010.
(Summary)
Congenital ventricular diverticulum (CVD) in adults is a rare cardiac malformation, which includes fibrous type congenital ventricular aneurysm (CVA). CVA is often clinically asymptomatic and shows no abnormality in the electrocardiogram or chest X-ray. However, some cases of sudden death resulting from ventricular tachycardia, cardiac embolism or ventricular rupture have been reported. Therefore, physicians should perform further cardiac imaging studies to detect a CVA if ventricular arrhythmia originating from the left ventricle is observed. Here, we report two successfully followed cases of CVA which were diagnosed from premature ventricular contractions.
Michihiro Nakamura, Shuji Ozaki, Masahiro Abe, Hiroyuki Doi, Toshio Matsumoto and Kazunori Ishimura : Size-controlled synthesis, surface functionalization, and biological applications of thiol-organosilica particles., Colloids and Surfaces B:Biointerfaces, Vol.79, No.1, 19-26, 2010.
(Summary)
Thiol-organosilica particles of a narrow size distribution, made from 3-mercaptopropyltrimethoxysilane (MPMS), were prepared by means of a one-pot synthesis. We examined three synthetic conditions at high temperature (100 degrees C), including the Stöber synthesis and two entirely aqueous syntheses. Under all conditions, the sizes of MPMS particles were well controlled, and the average of the coefficient of variation for the size distribution was less than 20%. The incubation times required for formation of MPMS particles were shorter at high temperature than at low temperature. MPMS particles internally functionalized with fluorescent dye were also prepared by means of the same one-pot synthesis. On flow cytometry analysis these MPMS particles showed distinct peaks of scattering due to well-controlled sizes of particles as well as due to fluorescence signals. Real-time observation of interaction between fluorescent MPMPS particles and cultured cells could be observed under fluorescent microscopy with bright light. The surface of the as-prepared MPMS particles contained exposed mercaptopropyl residues, and the ability to adsorb proteins was at least 6 times higher than that of gold nanopaticles. In addition, fluorescein-labeled proteins adsorbed to the surface of the particles were quantitatively detected at the pg/ml level by flow cytometry. MPMS particles surface functionalized with anti-CD20 antibody using adsorption could bind with lymphoma cells expressing CD20 specifically. In this paper, we demonstrated the possibility of size-controlled thiol-organosilica particles for wild range of biological applications.
BACKGROUND: Multiple myeloma (MM) expands almost exclusively in the bone marrow and generates devastating bone lesions, in which bone formation is impaired and osteoclastic bone resorption is enhanced. TGF-beta, a potent inhibitor of terminal osteoblast (OB) differentiation, is abundantly deposited in the bone matrix, and released and activated by the enhanced bone resorption in MM. The present study was therefore undertaken to clarify the role of TGF-beta and its inhibition in bone formation and tumor growth in MM. METHODOLOGY/PRINCIPAL FINDINGS: TGF-beta suppressed OB differentiation from bone marrow stromal cells and MC3T3-E1 preosteoblastic cells, and also inhibited adipogenesis from C3H10T1/2 immature mesenchymal cells, suggesting differentiation arrest by TGF-beta. Inhibitors for a TGF-beta type I receptor kinase, SB431542 and Ki26894, potently enhanced OB differentiation from bone marrow stromal cells as well as MC3T3-E1 cells. The TGF-beta inhibition was able to restore OB differentiation suppressed by MM cell conditioned medium as well as bone marrow plasma from MM patients. Interestingly, TGF-beta inhibition expedited OB differentiation in parallel with suppression of MM cell growth. The anti-MM activity was elaborated exclusively by terminally differentiated OBs, which potentiated the cytotoxic effects of melphalan and dexamethasone on MM cells. Furthermore, TGF-beta inhibition was able to suppress MM cell growth within the bone marrow while preventing bone destruction in MM-bearing animal models. CONCLUSIONS/SIGNIFICANCE: The present study demonstrates that TGF-beta inhibition releases stromal cells from their differentiation arrest by MM and facilitates the formation of terminally differentiated OBs, and that terminally differentiated OBs inhibit MM cell growth and survival and enhance the susceptibility of MM cells to anti-MM agents to overcome the drug resistance mediated by stromal cells. Therefore, TGF-beta appears to be an important therapeutic target in MM bone lesions.
Shusuke Yagi, Masashi Akaike, Ken-ichi Aihara, Kazue Ishikawa, Takashi Iwase, Yasumasa Ikeda, Takeshi Soeki, Sumiko Yoshida, Yuka Sumitomo-Ueda, Toshio Matsumoto and Masataka Sata : Endothelial nitric oxide synthase-independent protective action of statin against angiotensin II-induced atrial remodeling via reduced oxidant injury., Hypertension, Vol.55, No.4, 918-923, 2010.
(Summary)
Activation of the renin-angiotensin system exacerbates atrial remodeling, leading to atrial fibrillation and thrombosis, especially in a condition with decreased NO bioavailability. Recently, it has been reported that statins reduce the incidence of atrial fibrillation through attenuation of atrial remodeling; however, the mechanisms have not been completely elucidated. Therefore, we aimed to clarify the beneficial effect of statin on atrial remodeling in condition with reduced NO bioavailability. Endothelial NO synthase(-/-) mice were sham operated or infused with angiotensin II (Ang II) via an osmotic minipump for 2 weeks, and Ang II-infused mice were divided into 3 treatment groups: pitavastatin, Tempol (a free radical scavenger), or vehicle. Echocardiography and electrocardiography showed that Ang II infusion caused left atrial enlargement and a high incidence of atrial fibrillation, whereas pitavastatin and Tempol prevented these abnormalities. In histological analysis, Ang II-induced atrial interstitial fibrosis, perivascular fibrosis, and cardiomyocyte hypertrophy were all attenuated by pitavastatin and Tempol. Immunohistochemical staining showed that Ang II downregulated thrombomodulin and tissue factor pathway inhibitor and upregulated tissue factor and plasminogen activator inhibitor 1 in the left atrium and that pitavastatin and Tempol corrected the thrombogenic condition. Moreover, pitavastatin and Tempol reduced Ang II-induced atrial superoxide production and atrial transforming growth factor-beta1 expression and Smad 2/3 phosphorylation. Atrial rac1-GTPase activity, known to activate NADPH oxidase, was attenuated by pitavastatin but not by Tempol. In conclusion, pitavastatin exerts endothelial NO synthase-independent protective actions against Ang II-induced atrial remodeling and atrial fibrillation with enhanced thrombogenicity through suppression of oxidant injury.
(Keyword)
Analysis of Variance / Angiotensin II / Animals / Antioxidants / Atrial Fibrillation / Blood Pressure / Blotting, Western / Cardiomegaly / Cyclic N-Oxides / Echocardiography / Fibrosis / Heart Atria / Heart Rate / Hydroxymethylglutaryl-CoA Reductase Inhibitors / Male / Mice / Mice, Knockout / Myocytes, Cardiac / Nitric Oxide Synthase Type III / Oxidative Stress / Quinolines / Renin-Angiotensin System / Reverse Transcriptase Polymerase Chain Reaction / Signal Transduction / Smad2 Protein / Smad3 Protein / Spin Labels / Transforming Growth Factor beta1
Shusuke Yagi, Masashi Akaike, Ken-ichi Aihara, Takashi Iwase, Kazue Ishikawa, Sumiko Yoshida, Yuka Sumitomo-Ueda, Kenya Kusunose, Toshiyuki Niki, Koji Yamaguchi, Kunihiko Koshiba, Yoichiro Hirata, Munkhbaatar Dagvasumberel, Yoshio Taketani, Noriko Tomita, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Toshio Matsumoto and Masataka Sata : Ezetimibe ameliorates metabolic disorders and microalbuminuria in patients with hypercholesterolemia., Journal of Atherosclerosis and Thrombosis, Vol.17, No.2, 173-180, 2010.
(Summary)
AIM: Ezetimibe, an inhibitor of Niemann-Pick C1-like 1 protein, has been shown to reduce the intestinal absorption of cholesterol. We investigated whether it also has beneficial effects on metabolic disorder and/or renal insufficiency in patients with hypercholesterolemia. METHODS: Ezetimibe was administered to 38 Japanese patients with hypercholesterolemia to obtain appropriate low-density lipoprotein cholesterol (LDL-chol) levels. Age- and sex-matched patients with hypercholesterolemia (n=38) were the controls. We evaluated the effects of ezetimibe before and 4 to 8 weeks after ezetimibe treatment. RESULTS: Ezetimibe significantly decreased LDL-chol levels and metabolic syndrome-related factors, including body weight, waist circumference, blood pressure; homeostasis model assessment insulin resistance (HOMA-IR), and urinary albumin excretion, were significantly reduced. In addition, it decreased the level of high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor (TNF)-alpha, the urinary excretion of 8-hydroxy-2'-deoxyguanosine, a parameter of oxidative stress, and increased the urinary excretion of nitrate and nitrite (NOx). In the controls we observed no such changes. Excepting the decrease in the serum TNF-alpha level, the effects of ezetimibe were not correlated with decreased LDL-chol levels. CONCLUSION: Ezetimibe ameliorated the status of metabolic syndrome and microalbuminuria, reduced inflammation and oxidative stress, and increased nitric oxide bioavailability in a LDL-chol reduction-dependent and -independent manner.
Masatomo Mihara, Ken-ichi Aihara, Yasumasa Ikeda, Sumiko Yoshida, Mizuho Kinouchi, Kiyoe Kurahashi, Yuichi Fujinaka, Masashi Akaike and Toshio Matsumoto : Inhibition of thrombin action ameliorates insulin resistance in type 2 diabetic db/db mice., Endocrinology, Vol.151, No.2, 513-519, 2009.
(Summary)
The binding of thrombin to its receptor stimulates inflammatory cytokines including IL-6 and monocyte chemoattractant protein-1 (MCP-1); both are associated with the development of insulin resistance. Because increased adiposity enhanced the expression of coagulation factor VII that stimulates the coagulation pathway in adipose tissue, we tested whether the inhibition of thrombin action ameliorates insulin resistance in obese diabetic (Lpr(-/-):db/db) mice. The 4-wk administration of argatroban, a selective thrombin inhibitor, reduced fasting plasma glucose and ameliorated insulin resistance in these mice. It also reduced adipocyte size and macrophage infiltration into adipose tissue. The aberrant gene expression of MCP-1, IL-6, adiponectin, and factor VII and suppressed insulin receptor substrate-1-Akt signaling in adipose tissue of db/db mice were reversed by argatroban treatment. These results demonstrate that increased adiposity enhances the production of thrombin in adipose tissue by stimulating factor VII expression and suggest that increased thrombin activity in adipose tissue plays an important role in the development of insulin resistance via enhancing MCP-1 production, leading to macrophage infiltration and insulin receptor substrate-1-Akt pathway inactivation.
Masahiro Hiasa, Masahiro Abe, Ayako Nakano, Asuka Oda, Hiroe Amou, Shinsuke Kido, Kyoko Takeuchi, Kumiko Kagawa, Kenichiro Yata, Toshihiro Hashimoto, Shuji Ozaki, Kenzo Asaoka, Eiji Tanaka, Keiji Moriyama and Toshio Matsumoto : GM-CSF and IL-4 induce dendritic cell differentiation and disrupt osteoclastogenesis through M-CSF receptor shedding by up-regulation of TNF-{alpha} converting enzyme (TACE), Blood, Vol.114, No.20, 4517-4526, 2009.
(Summary)
Monocytes give rise to macrophages, osteoclasts (OCs), and dendritic cells (DCs). M-CSF and RANK ligand induce OC differentiation from monocytes, while GM-CSF and IL-4 trigger monocytic differentiation into DCs. These two differentiation pathways occur in a mutually exclusive manner. However, regulatory mechanisms for the polarization of monocytic differentiation are still unclear. The present study was undertaken to clarify the mechanism of triggering the deflection of OC and DC differentiation from monocytes. GM-CSF and IL-4 abolished monocytic differentiation into OCs while inducing DC differentiation even in the presence of M-CSF and RANK ligand. GM-CSF and IL-4 in combination potently up-regulate TNF-alpha converting enzyme (TACE) expression and activity in monocytes, causing ectodomain shedding of the membrane-bound M-CSF receptor, resulting in the disruption of its phosphorylation by M-CSF as well as the induction of osteoclastogenesis from monocytes by M-CSF and RANK ligand. Interestingly, TACE inhibition robustly causes the resumption of the surface expression of M-CSF receptors on monocytes, which facilitates M-CSF-mediated phosphorylation of M-CSF receptors and macrophage/OC differentiation while impairing GM-CSF and IL-4-mediated DC differentiation from monocytes. These results reveal a novel proteolytic regulation of M-CSF receptor expression in monocytes to control M-CSF signaling and monocytic differentiation into macrophage/OC-lineage cells or DCs.
Mitsunori Fujimura, Masashi Akaike, Takashi Iwase, Sumiko Yoshida, Yuka Sumitomo, Shusuke Yagi, Yasumasa Ikeda, Shunji Hashizume, Ken-ichi Aihara, Takeshi Nishiuchi, Yoshio Yasumura and Toshio Matsumoto : Decrease in plasma brain natriuretic peptide level in the early phase after the start of carvedilol therapy is a novel predictor of long-term outcome in patients with chronic heart failure., Acta Cardiologica, Vol.64, No.5, 589-595, 2009.
(Summary)
OBJECTIVE: The purpose of the present study was to determine whether change in plasma brain natriuretic peptide (BNP) level at an early phase of carvedilol therapy is a predictor of improvement in cardiac function and long-term prognosis in patients with systolic chronic heart failure (CHF). METHODS AND RESULTS: Neurohumoral factors and haemodynamics were examined in 64 patients with systolic CHF (left ventricular ejection fraction (LVEF) below 45%) before and one month (early phase) and 3 to 6 months (late phase) after the start of carvedilol therapy. These patients were followed up for a mean period of 57 months. Plasma BNP levels were already decreased in the early phase before improvement of LVEF in response to carvedilol therapy. Univariate and multivariate linear regression analyses showed that Delta log brain natriuretic peptide (BNP)E (= log BNP at baseline--log BNP at early phase) (P < 0.0001) was a significant independent predictor of improvement in LVEF in the late phase. Cardiac events occurred in I I patients during the follow-up period. In addition, multivariate Cox proportional hazards regression analysis showed that Delta log BNPE (P = 0.0045) and systolic blood pressure at baseline (P = -0.048) were significant independent predictors of the development of cardiac events. CONCLUSIONS: Decrease in plasma BNP level in the early phase of carvedilol therapy is a novel predictor of not only improvement of LVEF in the late phase but also prognosis in patients with systolic CHF.
Ken-ichi Aihara, Hiroyuki Azuma, Masashi Akaike, Hirotsugu Kurobe, Nobuyuki Takamori, Yasumasa Ikeda, Yuka Sumitomo, Sumiko Yoshida, Shusuke Yagi, Takashi Iwase, Kazue Ishikawa, Masataka Sata, Tetsuya Kitagawa and Toshio Matsumoto : Heparin cofactor II is an independent protective factor against peripheral arterial disease in elderly subjects with cardiovascular risk factors., Journal of Atherosclerosis and Thrombosis, Vol.16, No.2, 127-134, 2009.
(Summary)
AIM: Heparin cofactor II (HCII) specifically inactivates thrombin action at the injured vascular wall. We have reported that HCII is a protective factor against coronary in-stent restenosis and carotid atherosclerosis; however, it is unclear whether there is any correlation between plasma HCII levels and the development of peripheral arterial disease (PAD). METHODS: Plasma HCII activity and the ankle brachial pressure index (ABI) were determined in 494 elderly subjects with cardiovascular risk factors. PAD was diagnosed by ABI below 0.9, and 62 subjects were diagnosed with PAD. The relationship between factors that affect cardiovascular events and the prevalence of PAD was statistically evaluated. RESULTS: Mean HCII activity in PAD subjects was significantly lower than in non-PAD subjects (87.5+/-19.7% v.s. 94.6+/-17.8%, p=0.009). Multivariate logistic regression analysis showed that age (odds ratio [OR]: 1.062, p=0.0016), current smoking (OR 3.028, p=0.002) and diabetes mellitus (OR 2.656, p=0.008) were independent and progressive determinants of PAD. In contrast, HCII was an independent inhibitory factor of PAD (OR: 0.982, p=0.048). CONCLUSIONS: Plasma HCII activity is inversely related to the prevalence of PAD. HCII may function as the sole protective factor against PAD in elderly people with cardiovascular risk factors.
(Keyword)
Aged / Aged, 80 and over / Cardiovascular Diseases / Female / Heparin Cofactor II / Humans / Male / Middle Aged / Peripheral Vascular Diseases / Prevalence / Protective Agents / Risk Factors
Ken-ichi Kitazoe, Masahiro Abe, Masahiro Hiasa, Asuka Oda, Hiroe Amou, Takeshi Harada, Ayako Nakano, Kyoko Takeuchi, Toshihiro Hashimoto, Ken-ichiro Yata, Shuji Ozaki and Toshio Matsumoto : Valproic acid exerts anti-tumor as well as anti-angiogenic effects on myeloma., International Journal of Hematology, Vol.89, No.1, 45-57, 2008.
(Summary)
Multiple myeloma is still an incurable disease, most commonly occurring in the elderly. The myeloma-induced bone marrow microenvironment protects myeloma cells from drug-induced apoptosis. Therefore, the development of novel and tolerable therapeutic alternatives to overcome the drug resistance is an important clinical issue. Valproic acid (VPA), a safe and widely used anti-epileptic agent, is revisited as a class I- and IIa-specific histone deacetylase inhibitor. In the present study, we evaluated the effect as well as a mechanism of actions of VPA on myeloma cell growth and survival, with special reference to the myeloma-induced bone marrow microenvironment. VPA at therapeutic concentrations for epilepsy induced cell death in primary CD138-positive myeloma cells as well as myeloma cell lines, but not in CD138-negative bone marrow cells. VPA suppressed osteoclastogenesis as well as osteoclast-mediated myeloma cell growth. VPA also inhibited vascular tubule formation enhanced by co-cultures of myeloma cells and osteoclasts in concert with thalidomide. In addition, VPA induced both caspase-dependent and -independent cell death in myeloma cells, and potentiated the anti-myeloma effects of melphalan and dexamethasone. Collectively, VPA is suggested to exert multi-factorial anti-myeloma actions, and may serve as a safe adjuvant to be included in conventional chemotherapies against myeloma.
Lactobacillus (LB) is a gram-positive rod-shaped bacterium that inhabits the oral cavity, gastrointestinal tract, vagina and nasal cavity. Although LB plays a role in the prevention of infections caused by pathogenic bacteria, it causes some critical infectious diseases such as infective endocarditis (IE). IE due to LB is rare; however, early diagnosis and early treatment are important because of its high mortality rate. We report the onset of IE after otologic treatment in a heavy drinker of alcohol, the second case of IE due to LB in Japan.
Itsuro Endo, Seiji Fukumoto, Keiichi Ozono, Noriyuki Namba, Hiroyuki Tanaka, Daisuke Inoue, Masanori Minagawa, Toshitsugu Sugimoto, Mika Yamauchi, Toshimi Michigami and Toshio Matsumoto : Clinical usefulness of measurement of fibroblast growth factor 23 (FGF23) in hypophosphatemic patients: proposal of diagnostic criteria using FGF23 measurement., Bone, Vol.42, No.6, 1235-1239, 2008.
(Summary)
Fibroblast growth factor 23 (FGF23) plays important roles in the development of hypophosphatemic diseases such as tumor-induced osteomalacia (TIO) and X-linked hypophosphatemic rickets/osteomalacia (XLH). However, clinical usefulness of measurement of FGF23 has not been established. The objective of this study is to examine the importance of FGF23 measurement in the diagnosis of hypophosphatemic diseases. Biochemical parameters concerning phosphate metabolism were analyzed in a cross-sectional study. 32 patients with TIO, 28 patients with XLH and 16 hypophosphatemic patients with other causes including vitamin D deficiency, Fanconi's syndrome and Cushing's syndrome were studied. In patients with TIO and XLH, FGF23 was above the upper limit of the reference range in most patients irrespective of medical treatment. The lowest FGF23 in these patients was 38.0 pg/ml. FGF23 in hypophosphatemic patients with other causes was undetectable (less than 3 pg/ml) in 12 patients and the highest FGF23 in this group was 23.9 pg/ml. Relationship between phosphate and FGF23 indicated that TIO and XLH are diseases with high FGF23 and hypophosphatemia judged by age-dependent reference ranges for serum phosphate. FGF23 measurement is useful for differential diagnosis of hypophosphatemic diseases caused by excess actions of FGF23 and other etiologies. High FGF23 with low phosphate judged by age-dependent reference ranges for phosphate establishes the diagnosis of diseases caused by excess actions of FGF23.
Toshiyuki Obata, Ichiro Yokota, Kazuhiro Yokoyama, Eiji Okamoto, Yoshiko Kanezaki, Yoshinori Tanaka, Hiroshi Maegawa, Kiyoshi Teshigawara, Fumiko Hirota, Tomoyuki Yuasa, Kazuhiro Kishi, Atsushi Hattori, Seiichi Hashida, Kazuhiko Masuda, Mitsuru Matsumoto, Toshio Matsumoto, Atsunori Kashiwagi and Yousuke Ebina : Soluble insulin receptor ectodomain is elevated in the plasma of patients with diabetes mellitus., Diabetes, Vol.56, No.8, 2028-2035, 2007.
(Summary)
Insulin binds to the alpha-subunit of the insulin receptor (IRalpha) and subsequently exerts its effects in the cells. The soluble ectodomains of several receptors have been found to circulate in the plasma. Therefore, we hypothesized that soluble human insulin receptor (hIR) ectodomain (alpha-subunit and a part of beta-subunit) may exist in the plasma of diabetic patients. We identified soluble hIR ectodomain in human plasma by a two-step purification followed by immunoblotting and gel-filtration chromatography. Furthermore, we established an hIRalpha-specific enzyme-linked immunosorbent assay and measured the plasma IRalpha levels in patients with diabetes. We also investigated this phenomenon in streptozotocin-induced diabetic hIR transgenic mice. Soluble hIRalpha, but not intact hIRbeta or whole hIR, exists in human plasma. The plasma IRalpha levels were significantly higher in type 1 (2.00 +/- 0.60 ng/ml; n = 53) and type 2 (2.26 +/- 0.80; n = 473) diabetic patients than in control subjects (1.59 +/- 0.40 ng/ml; n = 123 (P < 0.001 vs. control). Plasma IRalpha level was positively correlated with blood glucose level, and 10-20% of the insulin in plasma bound to hIRalpha. In the in vivo experiments using diabetic hIR transgenic mice, hyperglycemia was confirmed to increase the plasma hIRalpha level and the half-life estimated to be approximately 6 h. We propose that the increased soluble IR ectodomain level appears to be a more rapid glycemic marker than A1C or glycoalbumin.
Heparin cofactor II (HCII) specifically inhibits thrombin action at sites of injured arterial wall, and patients with HCII deficiency exhibit advanced atherosclerosis. However, the in vivo effects and the molecular mechanism underlying the action of HCII during vascular remodeling remain elusive. To clarify the role of HCII in vascular remodeling, we generated HCII-deficient mice by gene targeting. In contrast to a previous report, HCII(-/-) mice were embryonically lethal. In HCII(+/-) mice, prominent intimal hyperplasia with increased cellular proliferation was observed after tube cuff and wire vascular injury. The number of protease-activated receptor-1-positive (PAR-1-positive) cells was increased in the thickened vascular wall of HCII(+/-) mice, suggesting enhanced thrombin action in this region. Cuff injury also increased the expression levels of inflammatory cytokines and chemokines in the vascular wall of HCII(+/-) mice. The intimal hyperplasia in HCII(+/-) mice with vascular injury was abrogated by human HCII supplementation. Furthermore, HCII deficiency caused acceleration of aortic plaque formation with increased PAR-1 expression and oxidative stress in apoE-KO mice. These results demonstrate that HCII protects against thrombin-induced remodeling of an injured vascular wall by inhibiting thrombin action and suggest that HCII is potentially therapeutic against atherosclerosis without causing coagulatory disturbance.
(Keyword)
Animals / Base Sequence / Blood Vessels / DNA Primers / Embryo Loss / Female / Gene Targeting / Genes, Lethal / Genotype / Heparin Cofactor II / Heterozygote / Homozygote / Male / Mice / Mice, Inbred C57BL / knockout mice / Pregnancy
Youichi Tanaka, Masahiro Abe, Masahiro Hiasa, Asuka Oda, Hiroe Amou, Ayako Nakano, Kyoko Takeuchi, Kenichi Kitazoe, Shinsuke Kido, Daisuke Inoue, Keiji Moriyama, Toshihiro Hashimoto, Shuji Ozaki and Toshio Matsumoto : Myeloma Cell-Osteoclast Interaction Enhances Angiogenesis Together with Bone Resorption: A Role for Vascular Endothelial Cell Growth Factor and Osteopontin, Clinical Cancer Research, Vol.13, No.3, 816-823, 2007.
(Summary)
Similar to osteoclastogenesis, angiogenesis is enhanced in the bone marrow in myeloma in parallel with tumor progression. We showed previously that myeloma cells and osteoclasts are mutually stimulated to form a vicious cycle to lead to enhance both osteoclastogenesis and tumor growth. The present study was undertaken to clarify whether myeloma cell-osteoclast interaction enhances angiogenesis and whether there is any mutual stimulation between osteoclastogenesis and angiogenesis. Myeloma cells and monocyte-derived osteoclasts were cocultured, and angiogenic activity produced by the cocultures was assessed with in vitro vascular tubule formation assays and human umbilical vascular endothelial cell (HUVEC) migration and survival. Osteoclastogenic activity was determined with rabbit bone cell cultures on dentine slices. Myeloma cells and osteoclasts constitutively secrete proangiogenic factors, vascular endothelial growth factor (VEGF) and osteopontin, respectively. A cell-to-cell interaction between myeloma cells and osteoclasts potently enhanced vascular tubule formation. Blockade of both VEGF and osteopontin actions almost completely abrogated such vascular tubule formation as well as migration and survival of HUVECs enhanced by conditioned medium from cocultures of myeloma cells and osteoclasts. Furthermore, these factors in combination triggered the production of osteoclastogenic activity by HUVEC. Osteoclast-derived osteopontin and VEGF from myeloma cells cooperatively enhance angiogenesis and also induce osteoclastogenic activity by vascular endothelial cells. These observations suggest the presence of a close link between myeloma cells, osteoclasts, and vascular endothelial cells to form a vicious cycle between bone destruction, angiogenesis, and myeloma expansion.
Masahiro Abe, Shinsuke Kido, Masahiro Hiasa, Nakano Ayako, Oda Asuka, Amou Hiroe and Toshio Matsumoto : BAFF and APRIL as osteoclast-derived survival factors for myeloma cells: a rationale for TACI-Fc tratment in patients with multiple myeloma., Leukemia, Vol.20, No.7, 1313-1315, 2006.
(Keyword)
B-Cell Activating Factor / Cell Survival / Humans / Immunoglobulin Fc Fragments / Multiple Myeloma / Osteoclasts / Transmembrane Activator and CAML Interactor Protein / Tumor Necrosis Factor Ligand Superfamily Member 13
Y. Kuroda, Takao Mitsui, M. Kunishige, Masayuki Shono, Masashi Akaike, H. Azuma and Toshio Matsumoto : Parkin enhances mitochondrial biogenesis in proliferating cells., Human Molecular Genetics, Vol.15, No.6, 883-895, 2006.
(Summary)
We describe a novel function of parkin, a RING protein, which is elaborately involved in mitochondrial biogenesis. Parkin was located within the mitochondrial organelle of proliferating cells. Anti-proliferative treatments released parkin from mitochondria to cytosol. Results of pharmacological treatments indicate that parkin was released from mitochondria when permeability transition pore was opened. The extra-mitochondrial localization was also observed in differentiated cells. In proliferating cells, transcription and replication of mitochondrial DNA was enhanced by parkin overexpression and attenuated by parkin suppression with siRNA. Parkin was associated with mitochondrial transcription factor A (TFAM) and enhanced TFAM-mediated mitochondrial transcription. These results indicate that parkin is involved in the regulation of mitochondrial transcription/replication other than the ubiquitin-mediated protein degradation system in proliferating cells.
Ali Jalili, Shuji Ozaki, Tomoko Hara, Hironobu Shibata, Toshihiro Hashimoto, Masahiro Abe, Yasuhiko Nishioka and Toshio Matsumoto : Induction of HM1.24 peptide specific cytotoxic T lymphocytes by using peripheral-blood stem-cell harvests in patients with multiple myeloma, Blood, Vol.106, No.10, 3538-3545, 2005.
(Summary)
HM1.24 antigen is preferentially overexpressed in multiple myeloma (MM) cells but not in normal cells. To explore the potential of HM1.24 as a target for cellular immunotherapy, we selected 4 HM1.24-derived peptides that possess binding motifs for HLA-A2 or HLA-A24 by using 2 computer-based algorithms. The ability of these peptides to generate cytotoxic T lymphocytes (CTLs) was examined in 20 healthy donors and 6 patients with MM by a reverse immunologic approach. Dendritic cells (DCs) were induced from peripheral-blood mononuclear cells of healthy donors or peripheral-blood stem-cell (PBSC) harvests from patients with MM, and autologous CD8(+) T cells were stimulated with HM1.24 peptide-pulsed DCs. Both interferon-gamma-producing and cytotoxic responses were observed after stimulation with either HM1.24-126 or HM1.24-165 peptides in HLA-A2 or HLA-A24 individuals. The peptide-specific recognition of these CTLs was further confirmed by tetramer assay and cold target inhibition assay. Importantly, HM1.24-specific CTLs were also induced from PBSC harvests from patients with MM and these CTLs were able to kill MM cells in an HLA-restricted manner. These results indicate the existence of functional DCs and HM1.24-specific CTL precursors within PBSC harvests and provide the basis for cellular immunotherapy in combination with autologous PBSC transplantation in MM.
Takashi Oshima, Masahiro Abe, Jin Asano, Tomoko Hara, Kenichi Kitazoe, Etsuko Sekimoto, Yoichi Tanaka, Hironobu Shibata, Toshihiro Hashimoto, Shuji Ozaki, Shinsuke Kido, Daisuke Inoue and Toshio Matsumoto : Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2, Blood, Vol.106, No.9, 3160-3165, 2005.
(Summary)
Multiple myeloma (MM) develops devastating bone destruction with enhanced bone resorption and suppressed bone formation. In contrast to enhanced osteoclastogenesis, little is known about the mechanism of impaired bone formation in MM. Because a canonical Wingless-type (Wnt) signaling pathway has recently been shown to play an important role in osteoblast differentiation, we examined whether MM cells affect a canonical Wnt pathway to suppress bone formation. Conditioned media from RPMI8226 and U266 MM cell lines and primary MM cells suppressed in vitro mineralization as well as alkaline phosphatase activity in osteoblasts induced by bone morphogenetic protein 2 (BMP-2). These cell lines constitutively produced a soluble Wnt inhibitor, secreted Frizzled-related protein 2 (sFRP-2), but not other Wnt inhibitors including sFRP-1, sFRP-3, and dickkopf 1 (DKK-1) at the protein level. Most MM cells from patients with advanced bone destructive lesions also expressed sFRP-2. Furthermore, exogenous sFRP-2 suppressed osteoblast differentiation induced by BMP-2, and immunodepletion of sFRP-2 significantly restored mineralized nodule formation in vitro, suggesting a predominant role for MM cell-derived sFRP-2 in the impairment of bone formation by MM. Thus, in addition to enhanced osteolysis, MM cells also suppress bone formation at least in part through an inhibition of the canonical Wnt pathway by secreting sFRP-2.
Hironobu Shibata, Masahiro Abe, Kenji Hiura, Javier Wilde, Keiji Moriyama, Toshiaki Sano, Ken-ichi Kitazoe, Toshihiro Hashimoto, Shuji Ozaki, Shingo Wakatsuki, Shinsuke Kido, Daisuke Inoue and Toshio Matsumoto : Malignant B-lymphoid cells with bone lesions express receptor activator of nuclear factor-kappaB ligand and vascular endothelial growth factor to enhance osteoclastogenesis., Clinical Cancer Research, Vol.11, No.17, 6109-6115, 2005.
(Summary)
Receptor activator of nuclear factor-kappaB ligand (RANKL) is a key mediator of osteoclastogenesis. Because certain types of tumor cells aberrantly express RANKL, and because bone destruction also develops in B-cell lymphomas of bone origin, we investigated RANKL expression and the mechanisms of osteoclastogenesis in B-lymphoid neoplasms. Immunohistochemistry of bone specimens resected from patients with primary B-cell lymphoma of bone with bone destruction revealed that lymphoma cells express RANKL as well as vascular endothelial cell growth factor (VEGF). The tumor cells isolated from the bone specimens enhanced osteoclastogenesis in vitro. In contrast, B-cell lymphoma infiltrating to the bone marrow without bone destruction did not express RANKL. Both RANKL and VEGF were expressed by a portion of B-lymphoid cell lines, including Daudi and IM-9. These RANKL-expressing tumor cells enhanced osteoclastogenesis from RAW264.7 cells and human monocyte-derived preosteoclasts in the absence of stromal cells/osteoblasts in a RANKL-dependent manner. Furthermore, conditioned media from Daudi cells enhanced transmigration of preosteoclasts that was inhibited by anti-VEGF antibody, suggesting that tumor cell-derived VEGF mediates recruitment of osteoclast precursors. Moreover, cocultures of B-lymphoid cell lines with osteoclasts enhanced the growth of B-lymphoid cells. Some malignant B cells aberrantly express functional RANKL as well as VEGF to enhance osteoclastogenesis. The coexpression of RANKL and VEGF may also contribute to the close cellular interactions with osteoclastic cells, thereby forming a vicious cycle between osteoclastic bone destruction and tumor expansion in bone.
Toshio Matsumoto, Takami Miki, Hiroshi Hagino, Toshitsugu Sugimoto, Sumiaki Okamoto, Takako Hirota, Yusuke Tanigawara, Yasufumi Hayashi, Masao Fukunaga, Masataka Shiraki and Toshitaka Nakamura : A New Active Vitamin D, ED-71, Increases Bone Mass in Osteoporotic Patients under Vitamin D Supplementation: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial, The Journal of Clinical Endocrinology and Metabolism, Vol.90, No.9, 5031-5036, 2005.
(Summary)
ED-71 has been shown to increase lumbar bone mineral density (BMD) in osteoporotic subjects. However, vitamin D insufficiency might have influenced the effect of ED-71 on BMD. Our objective was to examine whether ED-71 can increase BMD in osteoporotic patients under vitamin D supplementation. We conducted a randomized, double-blind, placebo-controlled clinical trial of 219 osteoporotic patients (49-87 yr of age). Interventions: Subjects were randomly assigned to receive placebo or 0.5, 0.75, or 1.0 microg/d ED-71 for 12 months. All the subjects received 200 or 400 IU/d vitamin D(3). We assessed changes in lumbar and hip BMD and bone turnover markers from baseline. Lumbar BMD increased with ED-71 treatment for 12 months (2.2, 2.6, and 3.1% from baseline and 2.9, 3.4, and 3.8% vs. placebo group in subjects receiving 0.5, 0.75, and 1.0 microg ED-71, respectively). Total hip BMD also increased with 0.75 and 1.0 microg ED-71 (-0.8, 0.6, and 0.9% from baseline and 0.1, 1.5, and 1.8% vs. placebo group in the 0.5, 0.75, and 1.0 microg ED-71 groups, respectively). Bone formation and resorption markers were suppressed by approximately 20% after 12 months of 0.75 and 1.0 microg ED-71 treatment. Transient hypercalcemia over 2.6 mmol/liter occurred in 7, 5, and 23% of subjects in the 0.5, 0.75, and 1.0 microg ED-71 groups, respectively, but none of them developed sustained hypercalcemia. These results demonstrate that ED-71 treatment at around 0.75 microg/d can effectively and safely increase lumbar and hip BMD in osteoporotic patients with vitamin D supplementation.
(Keyword)
Absorptiometry, Photon / Aged / Aged, 80 and over / Biological Markers / Bone Density / Bone Remodeling / Calcitriol / calcium / Dose-Response Relationship, Drug / Double-Blind Method / Female / Hip Joint / Hormones / Humans / Hypercalcemia / Lumbar Vertebrae / Male / Middle Aged / Osteoporosis / Patient Compliance / vitamin D
Androgen has anabolic effects on cardiac myocytes and has been shown to enhance left ventricular enlargement and function. However, the physiological and patho-physiological roles of androgen in cardiac growth and cardiac stress-induced remodeling remains unclear. We aimed to clarify whether the androgen-nuclear androgen receptor (AR) system contributes to the cardiac growth and angiotensin II (Ang II)-stimulated cardiac remodeling by using systemic AR-null male mice. AR knock-out (ARKO) male mice, at 25 weeks of age, and age-matched wild-type (WT) male mice were treated with or without Ang II stimulation (2.0 mg/kg/day) for 2 weeks. ARKO mice with or without Ang II stimulation showed a significant reduction in the heart-to-body weight ratio compared with those of WT mice. In addition, echocardiographic analysis demonstrated impairments of both the concentric hypertrophic response and left ventricular function in Ang II-stimulated ARKO mice. Western blot analysis of the myocardium revealed that activation of extracellular signal-regulated kinases (ERK) 1/2 and ERK5 by Ang II stimulation were lower in ARKO mice than those of WT mice. Ang II stimulation caused more prominent cardiac fibrosis in ARKO mice than in WT mice with enhanced expression of types I and III collagen and transforming growth factor-beta1 genes and with increased Smad2 activation. These results suggest that, in male mice, the androgen-AR system participates in normal cardiac growth and modulates cardiac adaptive hypertrophy and fibrosis during the process of cardiac remodeling under hypertrophic stress.
Takashi Iwase, Noritoshi Nagaya, Takafumi Fujii, Takefumi Itoh, Shinsuke Murakami, Toshio Matsumoto, Kenji Kangawa and Soichiro Kitamura : Comparison of angiogenic potency between mesenchymal stem cells and mononuclear cells in a rat model of hindlimb ischemia, Cardiovascular Research, Vol.66, No.3, 543-551, 2005.
(Summary)
OBJECTIVE: Mesenchymal stem cells (MSC) are pluripotent cells that differentiate into a variety of cells including endothelial cells and vascular smooth muscle cells. Although transplantation of bone marrow-derived mononuclear cells (MNC) has already been applied for the treatment of critical limb ischemia, little information is available regarding comparison of the angiogenic potency between MSC and MNC. Accordingly, we injected equal numbers of MSC or MNC in a rat model of hindlimb ischemia and compared their therapeutic potential. METHODS AND RESULTS: Immediately after creating hindlimb ischemia, rats were randomized to receive MSC transplantation (MSC group), MNC transplantation (MNC group), or vehicle infusion (Control group). Three weeks after transplantation, the laser Doppler perfusion index was significantly higher in the MNC group than in the Control group (0.69+/-0.1 vs. 0.57+/-0.06, P<0.01). Furthermore, there was a marked improvement in blood perfusion in the MSC group (0.81+/-0.08). Capillary density was highest in the MSC group. The number of transplanted cell-derived endothelial cells was higher in the MSC group than in the MNC group. Transplanted cell-derived vascular smooth muscle cells were detected only in the MSC group. In vitro, MSC were more tolerant to apoptotic stimulus (serum starvation and hypoxia) than MNC. CONCLUSIONS: MSC transplantation caused significantly greater improvement in hindlimb ischemia than MNC transplantation. Compared with MNC, MSC survived well under an ischemic environment, and differentiated into not only endothelial cells but also vascular smooth muscle cells. Thus, MSC transplantation may be a new therapeutic strategy for the treatment of severe peripheral vascular disease.
Kana Shichijo, Takao Mitsui, Makoto Kunishige, Yukiko Kuroda, Kenjiro Masuda and Toshio Matsumoto : Involvement of mitochondria in myasthenia gravis complicated with dermatomyositis and rheumatoid arthritis: a case report, Acta Neuropathologica, Vol.109, No.5, 539-542, 2005.
(Summary)
We report a 57-year-old male with myasthenia gravis complicated with dermatomyositis and rheumatoid arthritis without evidence of thymoma. He showed prominent muscle wasting and weakness in the four extremities and trunk in addition to swallowing disturbance. He showed intolerance to exercise on a bicycle ergometer, and muscle biopsy specimens demonstrated ragged-red fibers. An anti-acetylcholine receptor (AChR) antibody was detected in his serum but no anti-mitochondrial M2 component antibody was found. In contrast, results of immunohistochemical study indicated that his serum sample reacted to muscle mitochondria as well as AChR. These results indicate the presence of an unidentified anti-mitochondrial antibody that may be involved in the development of mitochondrial dysfunction in skeletal muscle of the present patient.
OBJECTIVE: We hypothesized that aspirin may exhibit its anti-atherosclerotic effects via mechanisms other than cyclooxygenase inhibition in platelets. METHODS AND RESULTS: Using enhanced subtraction hybridization analysis, we found in human umbilical vein endothelial cells (HUVECs) that aspirin up-regulates the expression of aminopeptidase N (APN/CD13) mRNA and its surface protein levels in a dose-dependent manner. Enzymatic activity of APN/CD13 on HUVECs was increased approximately 1.5-fold by 1 mmol L(-1) of aspirin, and treatment with bestatin, an inhibitor for APN/CD13 metalloprotease activity, attenuated the enhanced activities of APN/CD13. Since activated thrombin receptor is reported to be inactivated by APN/CD13 in vitro, protective actions of aspirin on HUVECs by thrombin stimulation were examined, resulting in the suppression of endothelin-1 and reactive oxygen species productions in HUVECs. These inhibitory actions of aspirin were partially abrogated by bestatin. CONCLUSIONS: Aspirin may exert its anti-atherothrombotic effects in part via the inhibition of thrombin action by up-regulating APN/CD13 on endothelial cells.
Hajime Nawata, Satoshi Soen, Ryoichi Takayanagi, Ikuo Tanaka, Kunio Takaoka, Masao Fukunaga, Toshio Matsumoto, Yasuo Suzuki, Hiroyuki Tanaka, Saeko Fujiwara, Takami Miki, Akira Sagawa, Yoshiki Nishizawa and Yoshiki Seino : Guidelines on the management and treatment of glucocorticoid-induced osteoporosis of the Japanese Society for Bone and Mineral Research(2004), Journal of Bone and Mineral Metabolism, Vol.23, No.2, 105-109, 2005.
Takashi Iwase, Noritoshi Nagaya, Takafumi Fujii, Takefumi Itoh, Hatsue Ishibashi-Ueda, Masakazu Yamagishi, Kunio Miyatake, Toshio Matsumoto, Soichiro Kitamura and Kenji Kangawa : Adrenomedullin enhances angiogenic potency of bone marrow transplantation in a rat model of hindlimb ischemia, Circulation, Vol.111, No.3, 356-362, 2005.
(Summary)
BACKGROUND: Previous studies have shown that adrenomedullin (AM) inhibits vascular endothelial cell apoptosis and induces angiogenesis. We investigated whether AM enhances bone marrow cell-induced angiogenesis. METHODS AND RESULTS: Immediately after hindlimb ischemia was created, rats were randomized to receive AM infusion plus bone marrow-derived mononuclear cell (MNC) transplantation (AM+MNC group), AM infusion alone (AM group), MNC transplantation alone (MNC group), or vehicle infusion (control group). The laser Doppler perfusion index was significantly higher in the AM and MNC groups than in the control group (0.74+/-0.11 and 0.69+/-0.07 versus 0.59+/-0.07, respectively, P<0.01), which suggests the angiogenic potency of AM and MNC. Importantly, improvement in blood perfusion was marked in the AM+MNC group (0.84+/-0.08). Capillary density was highest in the AM+MNC group, followed by the AM and MNC groups. In vitro, AM inhibited MNC apoptosis, promoted MNC adhesiveness to a human umbilical vein endothelial cell monolayer, and increased the number of MNC-derived endothelial progenitor cells. In vivo, AM administration not only enhanced the differentiation of MNC into endothelial cells but also produced mature vessels that included smooth muscle cells. CONCLUSIONS: A combination of AM infusion and MNC transplantation caused significantly greater improvement in hindlimb ischemia than MNC transplantation alone. This effect may be mediated in part by the angiogenic potency of AM itself and the beneficial effects of AM on the survival, adhesion, and differentiation of transplanted MNCs.
Tomonori Yoshida, Hiroyuki Azuma, Ken-ichi Aihara, Mitsunori Fujimura, Masashi Akaike, Takao Mitsui and Toshio Matsumoto : Vascular smooth muscle cell proliferation is dependent upon upregulation of mitochondrial transcription factor A (mtTFA) expression in injured rat carotid artery, Atherosclerosis, Vol.178, No.1, 39-47, 2005.
(Summary)
Consistent with the physiological response to increased energy demand in proliferating cells, the number of mitochondria is upregulated in synthetic states of vascular smooth muscle cells (VSMC) in atherosclerotic lesion. We hypothesized that mitochondrial transcription factor A (mtTFA), a prerequisite factor for the transcription and replication of mtDNA, may be upregulated in VSMC of injured rat carotid artery, and that inhibition of its expression can attenuate the intimal thickening. Changes of intimal thickening and mtTFA expression by a treatment with antisense oligodeoxynucleotides (ODN) for mtTFA were investigated in balloon-injured rat carotid artery model. The expression of mtTFA was upregulated as early as 3 h up to 7 days after balloon injury. Delivery of ansisense ODN for mtTFA from adventitia side to injured arterial wall caused a significant decrease in intima-to-media (I/M) ratio. Furthermore, the increase in immunoreactivity and mRNA expression of mtTFA in injured artery as well as the number of mitochondria in intimal VSMC was abrogated by antisense ODN treatment. These data demonstrate that expression of mtTFA is upregulated in intimal VSMC of injured rat carotid artery, and that suppression of mtTFA expression by antisense ODN can attenuate intimal thickening after balloon injury.
M Kunishige, Takao Mitsui, I Endo and Toshio Matsumoto : Dermatomyositis associated with impairment in both muscle aerobic and anaerobic function, Clinical Neuropathology, Vol.24, No.1, 32-35, 2005.
(Summary)
We report a 50-year-old Japanese woman with dermatomyositis in whom an anti-mitochondrial antibody was detected. Muscle biopsy demonstrated periodic acid Schiff- (PAS) positive vacuoles in addition to infiltrates of mononuclear cells. Histochemical analysis showed reduced phosphorylase activity. An aerobic exercise test demonstrated that the concentrations of serum lactate and pyruvate were elevated before corticosteroid therapy but decreased after the therapy. On the other hand, in forearm ischemic exercise tests, the responses of serum lactate and pyruvate were attenuated before corticosteroid therapy but recovered after the therapy. These findings indicate that an inflammatory mechanism interfered with myophosphorylase activity and muscle aerobic function.
H. Omori, Takao Mitsui, M. Kunishige, I. Endo, K. Takahashi and Toshio Matsumoto : Systemic muscular inflammation in a patient with recurrent orbital myositis, Clinical Neuropathology, Vol.24, No.4, 191-193, 2005.
(Summary)
We report a 53-year-old Japanese woman who had recurrent orbital myositis for 14 years. She exhibited mild muscle weakness in proximal limbs 13 years after the onset of orbital myositis. An electromyogram revealed myopathic potentials and denervation potentials in proximal limb muscles. Quadriceps biopsy showed infiltrates of mononuclear cells around intramuscular vessels and mild degenerative changes in muscle cells. These findings indicate that the present case belongs to the spectrum of localized nodular myositis.
(Keyword)
orbital myositis / orbital inflammatory pseudotumor / localized nodular myositisfocal / focal myositis
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● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 16033136
Naoki Kimura, Shigeto Kawai, Yasuko Kinoshita, Takahiro Ishiguro, Yumiko Azuma, Shuji Ozaki, Masahiro Abe, Masamichi Sugimoto, Yuichi Hirata, Tetsuro Orita, Hisafumi Okabe, Toshio Matsumoto and Masayuki Tsuchiya : 2D7 diabody bound to the α2 domain of HLA class I efficiently induces caspase-independent cell death against malignant and activated lymphoid cells, Biochemical and Biophysical Research Communications, Vol.325, No.4, 1201-1209, 2004.
(Summary)
A mouse monoclonal antibody (2D7 mAb), which specifically bound to the alpha2 domain of HLA class I, rapidly induces cell aggregation accompanied by weak cytotoxicity against ARH-77 cells, suggesting that 2D7 mAb had a potential for agonist antibody. In order to enhance this cytotoxicity, 2D7 mAb was engineered to be a small bivalent antibody fragment, 2D7 diabody. The resultant 2D7 diabody showed a strong cytotoxicity against ARH-77 cells. As a notable characteristic feature, the lethal effect of 2D7 diabody was quite rapid, mediated by a caspase-independent death pathway. Furthermore, 2D7 diabody also showed cytotoxicity against several leukemia and lymphoma cell lines, and mitogen-activated peripheral blood mononuclear cells (PBMC), but not for normal resting PBMC and adherent cell lines such as HUVEC. These results suggest that 2D7 diabody could be expected as a novel therapeutic antibody for hematological malignancies as well as inflammatory diseases.
(Keyword)
Agonist antibody / Diabody / HLA class I / cell death / Therapeutic antibody / Hematological malignancy
Masayuki Iki, Takashi Akiba, Toshio Matsumoto, Harumi Nishino, Sadanobu Kagamimori, Yoshiko Kagawa and Hideo Yoneshima : Reference database of biochemical markers of bone turnover for the Japanese female population. Japanese Population-based Osteoporosis (JPOS) Study, Osteoporosis International, Vol.15, No.12, 981-991, 2004.
(Summary)
The present study was conducted as a part of the Japanese Population-based Osteoporosis (JPOS) Study to establish reference values on the biochemical markers of bone turnover in the general Japanese female population over an applicable age range. The study recruited 3250 women aged 15-79 years, randomly selected from five municipalities throughout Japan, and obtained measurements of serum osteocalcin (OC) and bone-specific alkaline phosphatase (BAP); free and total forms of immunoreactive deoxypyridinoline, free pyridinolines and type I collagen cross-linked C-terminal telopeptide (CTx) in urine; serum intact parathyroid hormone (PTH) and 1,25 dihydroxy vitamin D (1,25 (OH)2D); and bone density at the spine, hip and distal forearm. After excluding subjects with apparent or suggested abnormalities affecting bone mass, 2535 (78%) subjects were further analyzed. The authors presented 5-year age-specific mean values of the markers and mean marker levels derived from women aged 30-44 years with normal bone density as a healthy young adult reference. Values of the markers decreased with increasing age before the age of 40, increased steeply among subjects in their 50s, and remained elevated in the elderly. Serum calcium, phosphorus, PTH and 1,25 (OH)2D levels were higher in postmenopausal women than in premenopausal women. However, 1,25 (OH)2D was lower among early postmenopausal subjects. The levels of OC, BAP, CTx, PTH and 1,25(OH)2D were significantly greater for women with osteoporosis than for those without. The diagnostic value of the markers was limited as the sensitivity and specificity ranged from 55% to 60%. These findings will aid health professionals in the correct assessment of bone turnover status in Japanese women over a wide range of age.
(Keyword)
Age-related change / Biochemical markers of bone turnover / Japanese women / Menopause-related change / Population-based epidemiologic study / Random sample
Daisuke Inoue, Shinsuke Kido and Toshio Matsumoto : Transcriptional Induction of FosB/FosB Gene by Mechanical Stress in Osteoblasts, The Journal of Biological Chemistry, Vol.279, No.48, 49795-49803, 2004.
(Summary)
Mechanical stress to bone plays a critical role in maintaining bone mass and strength. However, the molecular mechanism of mechanical stress-induced bone formation is not fully understood. In the present study, we demonstrate that FosB and its spliced variant DeltaFosB, which is known to increase bone mass by stimulating bone formation in vivo, is rapidly induced by mechanical loading in mouse hind limb bone in vivo and by fluid shear stress (FSS) in mouse calvarial osteoblasts in vitro both at the mRNA and protein levels. FSS induction of FosB/DeltaFosB gene expression was dependent on gadlinium-sensitive Ca(2+) influx and subsequent activation of ERK1/2. Analysis of the mouse FosB/DeltaFosB gene upstream regulatory region with luciferase reporter gene assays revealed that the FosB/DeltaFosB induction by FSS occurred at the transcriptional level and was conferred by a short fragment from -603 to -327. DNA precipitation assays and DNA decoy experiments indicated that ERK-dependent activation of CREB binding to a CRE/AP-1 like element (designated "CRE2") at the position of -413 largely contributed to the transcriptional effects of FSS. These results suggest that DeltaFosB participates in mechanical stress-induced intracellular signaling cascades that activate the osteogenic program in osteoblasts.
M Kunishige, Takao Mitsui, B. H. Tan, H. N. Leong, T Takasaki, I Kurane, A Mihara and Toshio Matsumoto : Preferential gray matter involvement in dengue myelitis, Neurology, Vol.63, No.10, 1980-1981, 2004.
YUKIKO WATANABE, HIROSHI OHSHIMA, KOH MIZUNO, CHIHARU SEKIGUCHI, MASAO FUKUNAGA, KENJIRO KOHRI, JÖRN RITTWEGER, DIETER FELSENBERG, Toshio Matsumoto and TOSHITAKA NAKAMURA : Intravenous Pamidronate Prevents Femoral Bone Loss and Renal Stone Formation During 90-Day Bed Rest, Journal of Bone and Mineral Research, Vol.19, No.11, 1771-1778, 2004.
(Summary)
Long-term bed rest has potential risks of bone loss and renal stone formation. We examined the effects of resistive exercise and intravenous pamidronate on BMD, bone turnover, urinary calcium, and renal stone formation in 25 healthy males during 90-day bed rest. Pamidronate prevented femoral bone loss and renal stone formation, but resistive exercise showed little effects. Long-term bed rest increases the risks of bone loss and urinary stone formation. Resistive exercise increases bone formation, and bisphosphonates reduce bone resorption. However, the effects of muscle exercise and bisphosphonates have not been examined side-by-side. The objectives of this study are to compare the effects of pamidronate with resistive exercise on BMD and renal stone formation during prolonged bed rest. Twenty-five male white volunteers, 26-45 years of age, were randomly assigned to the control (n = 9), exercise (n = 9), and pamidronate (n = 7) groups and underwent 90-day 6 degrees head-down tilt bed rest. Exercise group performed squats and heel raises on a flywheel device for 30 minutes every 3 days. Pamidronate (60 mg) was administered intravenously 14 days before bed rest. BMD of the head, forearm, lumbar spine, and proximal femur; biochemical bone markers; calcium (Ca) metabolism; and abdominal radiographs were examined during 90 days of bed rest and 360 days of reloading. In controls, proximal femoral BMD decreased, and bone resorption markers and urinary Ca increased during bed rest, along with development of renal stones in two of nine subjects. Resistive exercise increased bone formation but was unable to prevent femoral BMD decrease and increases in bone resorption and urinary Ca during bed rest, with formation of renal stones in four of nine subjects. Pamidronate maintained femoral BMD, reduced bone resorption and urinary Ca, and completely prevented renal stone formation. Resistive exercise increased bone formation but could not reduce bone resorption and the risk of renal stones. In contrast, inhibition of bone resorption by pamidronate could preserve bone mineral and reduce the risk of renal stone formation during prolonged bed rest.
(Keyword)
Adult / Alkaline Phosphatase / Bed Rest / Biological Markers / Bone Density / Bone Diseases, Metabolic / Bone Remodeling / Bone Resorption / Bone and Bones / calcium / Diet / Diphosphonates / Exercise / Exercise Test / Humans / Infusions, Intravenous / Kidney Calculi / Male / Middle Aged / Supine Position / Time Factors
Yukiho Tanimoto, Masahiko Yokozeki, Hiura Kenji, Kazuya Matsumoto, Hideki Nakanishi, Toshio Matsumoto, PJ Marie and Keiji Moriyama : A soluble form of fibroblast growth factor receptor 2 (FGFR2) with S252W mutation acts as an efficient inhibitor for the enhanced osteoblastic differentiation caused by FGFR2 activation In Apert syndrome., The Journal of Biological Chemistry, Vol.279, No.44, 45926-45934, 2004.
Masahiro Abe, Kenji Hiura, Javier Wilde, Atsushi Shioyasono, Keiji Moriyama, Toshihiro Hashimoto, Shinsuke Kido, Takashi Oshima, Hironobu Shibata, Shuji Ozaki, Daisuke Inoue and Toshio Matsumoto : Osteoclasts enhance myeloma cell growth and survival via cell-cell contact: a vicious cycle between bone destruction and myeloma expansion., Blood, Vol.104, No.8, 2484-2491, 2004.
(Summary)
Multiple myeloma (MM) expands in the bone marrow and causes devastating bone destruction by enhancing osteoclastic bone resorption in its vicinity, suggesting a close interaction between MM cells and osteoclasts (OCs). Here, we show that peripheral blood mononuclear cell-derived OCs enhanced growth and survival of primary MM cells as well as MM cell lines more potently than stromal cells, and that OCs protected MM cells from apoptosis induced by serum depletion or doxorubicin. OCs produced osteopontin (OPN) and interleukin 6 (IL-6), and adhesion of MM cells to OCs increased IL-6 production from OCs. In addition, IL-6 and OPN in combination enhanced MM cell growth and survival. However, the effects of OCs on MM cell growth and survival were only partially suppressed by a simultaneous addition of anti-IL-6 and anti-OPN antibodies and were completely abrogated by inhibition of cellular contact between MM cells and OCs. These results demonstrate that OCs enhance MM cell growth and survival through a cell-cell contact-mediated mechanism that is partially dependent on IL-6 and OPN. It is suggested that interactions of MM cells with OCs augment MM growth and survival and, thereby, form a vicious cycle, leading to extensive bone destruction and MM cell expansion.
Ken-ichi Aihara, Hiroyuki Azuma, Masashi Akaike, Yasumasa Ikeda, Michiko Yamashita, Toshiki Sudo, Hideki Hayashi, Yoshihisa Yamada, Fuminari Endoh, Mitsunori Fujimura, Tomonori Yoshida, Hiroshi Yamaguchi, Shunji Hashizume, Midori Kato, Kimihiro Yoshimura, Yoko Yamamoto, Shigeaki Kato and Toshio Matsumoto : Disruption of nuclear vitamin D receptor gene causes enhanced thrombogenicity in mice, The Journal of Biological Chemistry, Vol.279, No.34, 35798-35802, 2004.
(Summary)
Vitamin D metabolites influence the expression of various genes involved in calcium homeostasis, cell differentiation, and regulation of the immune system. Expression of these genes is mediated by the activation of the nuclear vitamin D receptor (VDR). Previous studies have shown that a hormonally active form of vitamin D, 1alpha,25-dihydroxyvitamin D3, exerts anticoagulant effects in cultured monocytic cells. To clarify whether activation of VDR plays any antithrombotic actions in vivo, hemostatic/thrombogenic systems were examined in normocalcemic VDR knock-out (KO) mice on a high calcium diet and compared with wild type and hypocalcemic VDRKO mice that were fed a regular diet. Platelet aggregation was enhanced significantly in normocalcemic VDRKO mice compared with wild type and hypocalcemic VDRKO mice. Aortic endothelial nitric-oxide (NO) synthase expression and urinary NOx excretions were reduced in hypocalcemic VDRKO mice, but not in normocalcemic VDRKO mice. Northern blot and RT-PCR analyses revealed that the gene expression of antithrombin in the liver as well as that of thrombomodulin in the aorta, liver and kidney was down-regulated in hypo- and normocalcemic VDRKO mice. Whereas tissue factor mRNA expression in the liver and kidney was up-regulated in VDRKO mice regardless of plasma calcium level. Furthermore, VDRKO mice manifested an exacerbated multi-organ thrombus formation after exogenous lipopolysaccharide injection regardless of the calcemic conditions. These results demonstrate that activation of nuclear VDR elicits antithrombotic effects in vivo, and suggest that the VDR system may play a physiological role in the maintenance of antithrombotic homeostasis.
A. Ohno, Takao Mitsui, I. Endo, M. Kunishige, T. Sigekiyo and Toshio Matsumoto : Dermatomyositis associated with Sjögren's syndrome: VEGF involvement in vasculitis, Clinical Neuropathology, Vol.23, No.4, 178-182, 2004.
(Summary)
Two patients with dermatomyositis complicated with Sjögren's syndrome (SjS), are reported. Both patients exhibited sensory-dominant polyneuropathy, compatible with neurologic involvement in SjS. Vascular endothelial growth factor (VEGF) levels were increased in their plasma. Histological examination demonstrated vasculitic changes in biopsied specimens of muscle and salivary glands from the patients, and VEGF was overexpressed in the vasculitic lesions. These findings suggest that VEGF overexpression was associated with the development of vasculopathy in skeletal muscle and salivary glands and possibly in the peripheral nervous system.
We analyzed the effects of corticosteroid on mitochondrial membrane potentials (DeltaPsi(m)), generation of reactive oxygen species (ROS), and apoptosis in a human rhabdomyosarcoma cell line, RD, and a dopaminergic neuroblastoma cell line, SH-SY5Y. The cell lines were cultured in the presence or absence of dexamethasone and superoxide dismutase (SOD) for up to 1 week. Dexamethasone treatment increased DeltaPsi(m), ROS generation, and apoptosis in proliferating RD cells. Treatment with SOD attenuated ROS generation and apoptosis, but not DeltaPsi(m). The increase in DeltaPsi(m) seemed to be the primary effect of dexamethasone on proliferating RD cells, which is probably mediated by mitochondrial transcription. In differentiated RD cells, but not differentiated SH-SY5Y cells, dexamethasone treatment showed a delayed effect of interfering with the DeltaPsi(m) and increasing ROS generation and apoptosis. Since these changes disappeared in the presence of SOD, dexamethasone primarily induced ROS generation, resulting in apoptosis. We speculate that this mechanism provides the basis of a pathophysiological model of corticosteroid myopathy.
Ken-ichi Aihara, Hiroyuki Azuma, Nobuyuki Takamori, Yasuhiko Kanagawa, Masashi Akaike, Mitsunori Fujimura, Tomonori Yoshida, Shunji Hashizume, Midori Kato, Hiroshi Yamaguchi, Shuji Kato, Yasumasa Ikeda, Tomoko Arase, Akira Kondo and Toshio Matsumoto : Heparin cofactor II is a novel protective factor against carotid atherosclerosis in elderly individuals., Circulation, Vol.109, No.22, 2761-2765, 2004.
(Summary)
Thrombin plays a crucial role in atherothrombotic changes. Because heparin cofactor II (HCII) inhibits thrombin actions after binding to dermatan sulfate at injured arterial walls, HCII may negatively regulate thrombin actions in vascular walls. We hypothesized that plasma HCII activity is a preventive factor against atherosclerotic changes, especially in elderly individuals who already have atherosclerotic vascular injuries. Maximum plaque thickness (MPT) in the carotid artery was measured by ultrasonography in 306 Japanese elderly individuals (154 men and 152 women; age, 40 to 91 years; 68.9+/-11.1 years, mean+/-SD). The relevance of cardiovascular risk factors including plasma HCII activity to the severity of MPT was statistically evaluated. Plasma HCII activity decreased with age. Simple linear regression analysis after adjustments for age and sex showed that lipoprotein(a), glycosylated hemoglobin A1c, and presence of diabetes mellitus significantly contributed to an increase in MPT values (r=0.119, P<0.05; r=0.196, P<0.001; and r=0.227, P<0.0001, respectively). In contrast, high-density lipoprotein (HDL) cholesterol and HCII activity were negatively correlated with MPT values (r=-0.117, P<0.05, and r=-0.202, P<0.0005, respectively). Multiple regression analysis revealed that plasma HCII activity and HDL cholesterol independently contributed to the suppression of MPT values and that the antiatherogenic contribution of HCII activity was stronger than that of HDL cholesterol (P<0.001 and P<0.05, respectively). These results suggest that HCII can be a novel and independent antiatherogenic factor. Moreover, HCII is a stronger predictive factor than HDL cholesterol against carotid atherosclerosis in elderly individuals.
(Keyword)
Adult / Aged / Aged, 80 and over / aging / Antithrombins / Cardiovascular Diseases / Carotid Artery Diseases / Female / Heparin Cofactor II / Humans / Male / Middle Aged / Regression Analysis / Risk Factors / Severity of Illness Index
Makoto Kunishige, Takao Mitsui, Yukiko Kuroda, Sumiko Yoshida, Masaaki Kosaka and Toshio Matsumoto : Expanding phenotype and clinical heterogeneity in patients with identical mutation of the parkin gene., European Neurology, Vol.51, No.3, 183-185, 2004.
Toshihiro Hashimoto, Masahiro Abe, Takashi Oshima, Hironobu Shibata, Shuji Ozaki, Daisuke Inoue and Toshio Matsumoto : Ability of myeloma cells to secrete macrophage inflammatory protein (MIP)-1α and MIP-1β correlates with lytic bone lesions in patients with multiple myeloma, British Journal of Haematology, Vol.125, No.1, 38-41, 2004.
(Summary)
Macrophage inflammatory protein (MIP)-1alpha and MIP-1beta have been identified as candidates for multiple myeloma (MM)-derived bone-resorbing factors. To validate the clinical relevance of these observations, we investigated correlations between the ability of MM cells to secrete these chemokines and the extent of MM bone lesions as well as levels of biochemical bone markers in patients with MM. Patients with multiple bone lesions exhibited higher MIP-1alpha and MIP-1beta secretion from MM cells along with elevated urinary deoxypyridinoline (Dpd), without significant elevation of serum bone-specific alkaline phosphatase (BALP) or osteocalcin compared with those with minimal bone lesions. MIP-1alpha and MIP-1beta levels correlated positively with urinary Dpd and serum BALP but not with serum osteocalcin. These results provide further evidence for a causal role of MIP-1alpha and MIP-1beta in the development of lytic bone lesions, and suggest that MM cells suppress osteoblastic bone formation to cause an imbalance of bone turnover and development of destructive bone lesions.
Yoshiko Kanezaki, Toshiyuki Obata, Rie Matsushima, Asako Minami, Tomoyuki Yuasa, Kazuhiro Kishi, Yoshimi Bando, Hisanori Uehara, Keisuke Izumi, Tasuku Mitani, Mitsuru Matsumoto, Yukari Takeshita, Yutaka Nakaya, Toshio Matsumoto and Yousuke Ebina : KATP Channel Knockout Mice Crossbred with Transgenic Mice Expressing a Dominant-Negative Form of Human Insulin Receptor have Glucose Intolerance but not Diabetes, Endocrine Journal, Vol.51, No.2, 133-144, 2004.
(Summary)
Impaired insulin secretion and insulin resistance are thought to be two major causes of type 2 diabetes mellitus. There are two kinds of diabetic model mice: one is a K(ATP) channel knockout (Kir6.2KO) mouse which is defective in glucose-induced insulin secretion, and the other is a transgenic mouse expressing the tyrosine kinase-deficient (dominant-negative form of) human insulin receptor (hIR(KM)TG), and which has insulin resistance in muscle and fat. However, all of these mice have no evidence of overt diabetes. To determine if the double mutant Kir6.2KO/hIR(KM)TG mice would have diabetes, we generated mutant mice by crossbreeding, which would show both impaired glucose-induced insulin secretion and insulin resistance in muscle and fat. We report here that: 1) blood glucose levels of randomly fed and 6 h fasted double mutant (Kir6.2KO/hIR(KM)TG) mice were comparable with those of wild type mice; 2) in intraperitoneal glucose tolerance test (ipGTT), Kir6.2KO/hIR(KM)TG mice had an impaired glucose tolerance; and 3) during ipGTT, insulin secretion was not induced in either Kir6.2KO/hIR(KM)TG or Kir6.2KO mice, while the hIR(KM)TG mice showed a more prolonged insulin secretion than did wild type mice; 4) hyperinsulinemic euglycemic clamp test revealed that Kir6.2KO, Kir6.2KO/hIR(KM)TG and hIR(KM)TG mice, showed decreased whole-body glucose disposal compared with wild type mice; 5) Kir6.2KO, but not Kir6.2KO/hIR(KM)TG mice had some obesity and hyperleptinemia compared with wild type mice. Thus, the defects in glucose-induced insulin secretion (Kir6.2KO) and an insulin resistance in muscle and fat (hIR(KM)TG) were not sufficient to lead to overt diabetes.
Daisuke Inoue and Toshio Matsumoto : Reduced AP-1 mediated transcription of interleukin-11 gene in marrow stromal cells as a mechanism of senile Osteoprosis: lessons from SAMP6, International Congress Series, Vol.1260, No.C, 61-65, 2004.
Nobuyuki Takamori, Hiroyuki Azuma, Midori Kato, Shunji Hashizume, Ken-ichi Aihara, Masashi Akaike, Katsuya Tamura and Toshio Matsumoto : High plasma heparin cofactor II activity is associated with reduced incidence of in-stent restenosis after percutaneous coronary intervention, Circulation, Vol.109, No.4, 481-486, 2004.
(Summary)
Thrombin plays an important role in the development of atherosclerosis and restenosis after percutaneous coronary intervention. Because heparin cofactor II (HCII) inhibits thrombin action in the presence of dermatan sulfate, which is abundantly present in arterial wall, HCII may affect vascular remodeling by modulating thrombin action. We hypothesized that patients with high plasma HCII activity may show a reduced incidence of in-stent restenosis (ISR). Sequential coronary arteries (n=166) with NIR stent (Boston Scientific Corp) implantation in 134 patients were evaluated before, immediately after, and at 6 months after percutaneous coronary intervention. Patients were divided into the following groups: high HCII (> or =110%, 45 lesions in 36 patients), normal HCII (> or =80% and <110%, 81 lesions in 66 patients), and low HCII (<80%, 40 lesions in 32 patients). Percent diameter stenosis at follow-up in the high-HCII group (18.7%) was significantly lower (P=0.046) than that in the normal-HCII group (30.3%) or the low-HCII group (29.0%). The ISR rate in the high-HCII group (6.7%) was significantly lower than that in the low-HCII group (30.0%) (P=0.0039). Furthermore, multivariate analysis demonstrated that high plasma HCII activity is an independent factor in reducing the incidence of angiographic restenosis (odds ratio, 0.953/1% increase of HCII; 95% CI, 0.911 to 0.998). The results demonstrate that HCII may have a hitherto unrecognized effect in inhibiting ISR. The effect of HCII may be mediated by inactivating thrombin in injured arteries, thereby inhibiting vascular smooth muscle cell migration and proliferation.
Naoko Matsui, Takao Mitsui, Itsuro Endo, Yasushi Oshima, Makoto Kunishige and Toshio Matsumoto : Dermatomyositis with peripheral nervous system involvement: activation of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) in vasculitic lesions, Internal Medicine, Vol.42, No.12, 1233-1239, 2003.
(Summary)
We describe two cases of dermatomyositis (DM) with nervous system involvement. Polyneuropathy was observed in both patients, and cerebral vasculitis was suspected in one patient. Histological examination of biopsied specimens of skeletal muscles, skin and sural nerves revealed vasculitis. Furthermore, vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) were overexpressed in vasculitic lesions. Although, VEGF and VEGFRs were not detected in biopsied specimens of skeletal muscle from normal subjects, they were observed in one of two patients with DM who did not exhibit neuropathy. These findings suggest the possibility that VEGF overproduction is associated with development of vasculitis in some cases of DM complicated with peripheral neuropathy.
Yukiko Hiasa, Makoto Kunishige, Takao Mitsui, Shunsuke Kondo, Rika Kuriwaka, Shizuka Shigekiyo, Takanori Kanematsu, Nobuo Satake, Yoshimi Bando, Akira Kondo, Itsuro Endo, Yasushi Oshima and Toshio Matsumoto : Complicated paraneoplastic neurological syndromes: a report of two patients with small cell or non-small cell lung cancer, Clinical Neurology and Neurosurgery, Vol.106, No.1, 47-49, 2003.
(Summary)
Paraneoplastic neurological syndromes are frequently associated in patients with small cell lung cancer (SCLC) and antineuronal antibodies are involved in the autoimmune mechanism. Multiple syndromes are sometimes complicated in a single patient with SCLC. However, little is known about non-SCLC-associated neurological manifestations. We report two patients with complicated paraneoplastic neurological syndromes. Patient 1 showed paraneoplastic limbic encephalitis (PLE), paraneoplastic sensory neuropathy (PSN) and Lambert-Eaton myasthenic syndrome (LEMS) associated with SCLC. Patient 2 developed opsoclonus-ataxia and probable PLE associated with non-SCLC. Analysis of various antineuronal antibodies revealed that anti-Hu and P/Q-type voltage-gated calcium channel (VGCC) antibodies were positive in Patient 1 but any antibodies were not in Patient 2. Brain MRI demonstrated high intensity signals in temporal lobes particularly on fluid-attenuated inversion recovery (FLAIR) or diffusion-weighted images. These findings suggest that complicated paraneoplastic neurological syndromes occur in non-SCLC as well as SCLC and that unidentified antineuronal autoantibodies may underlie the pathophysiology.
(Keyword)
Anti-Hu antibody / paraneoplastic limbic encephalitis / Lambert-Eaton myasthenic syndrome / opsoclonus-ataxia / small cell lung cancer
Takao Mitsui, Yoshifumi Umaki, Masakazu Nagasawa, Masashi Akaike, Satoshi Ohtsuka, Masaaki Odomi, Kenji Aki and Toshio Matsumoto : Motor neuron involvement in a patient with long-term corticosteroid administration, Internal Medicine, Vol.42, No.9, 862-866, 2003.
(Summary)
An asthmatic patient with corticosteroid treatment for 45 years presented with slowly progressive limb muscle atrophy. His muscle symptoms were involved in four limbs and tongue, and deep tendon reflexes were exaggerated. Biopsied muscle pathology indicated the presence of neurogenic muscular atrophy in combination with corticosteroid myopathy. Furthermore, 8-hydroxy-deoxyguanosine (8-OH-dG) was prominently increased in mitochondrial and nuclear DNA. An aerobic exercise test demonstrated remarkable serum lactate elevation, which was attenuated by the administration of coenzyme Q10. These findings are consistent with the assumption that long-term corticosteroid administration potentially induces not only myopathy but also motor neuron involvement as in mitochondrial diseases.
Yoshiko Kanezaki, Rie Matsushima, Toshiyuki Obata, Yutaka Nakaya, Toshio Matsumoto and Yousuke Ebina : Injection of the Insulin receptor alpha subunit increases blood glucose levels in mice, Biochemical and Biophysical Research Communications, Vol.309, No.3, 572-577, 2003.
(Summary)
Using the expression vector of the truncated human insulin receptor (hIR), we have constructed a stable Chinese hamster ovary (CHO) cell line which secretes the His-tagged alpha subunit (insulin-binding domain) of hIR into medium. To examine characteristics of the His-tagged hIRalpha, we purified the protein secreted from the CHO cells. The His-tagged hIRalpha was glycosylated and processed a dimer. The molecule bound insulin with an affinity similar to that of the intact hIR. The His-tagged full length of hIR was autophosphorylated by insulin stimulation in CHO cells. Injection of the purified His-tagged hIRalpha into veins of mice increased in the concentration of blood glucose within 30 min. The intraperitoneal glucose tolerance test (ipGTT) done after injection of the purified His-tagged hIRalpha showed evidence of a marked hyperglycemia. These findings provide direct evidence that the presence of hIRalpha in the blood stream inhibits insulin actions by binding with plasma insulin.
Makoto Kunishige, Takao Mitsui, Masashi Akaike, Masakazu Kawajiri, Masayuki Shono, Hisaomi Kawai and Toshio Matsumoto : Overexpressions of myoglobin and antioxidant enzymes in ragged-red fibers of skeletal muscle from patients with mitochondrial encephalomyopathy, Muscle & Nerve, Vol.28, No.4, 484-492, 2003.
(Summary)
To determine the relationship between myoglobin (Mb) and the defense system against reactive oxygen species in various myopathies, we performed immunohistochemical analyses of Mb and various antioxidant enzymes, including manganese superoxide dismutase (Mn-SOD), copper zinc SOD (CuZn-SOD), catalase (CAT), and glutathione peroxidase (GSH-Px). Biopsied muscle specimens were obtained from patients with chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayre syndrome (KSS), Duchenne muscular dystrophy (DMD), and polymyositis (PM). In patients with CPEO/KSS, stainings of Mb, SOD, CAT, and GSH-Px in nonatrophic ragged-red fibers (RRFs) were more intense than those in non-RRFs. These pronounced stainings corresponded to ragged-red lesions. The staining intensities of these antioxidant enzymes were significantly correlated with that of Mb (P < 0.001). Atrophic RRFs in specimens from patients with CPEO/KSS showed intense stainings of these antioxidant enzymes but not intense staining of Mb. In specimens from patients with DMD/PM, the antioxidant enzymes but not Mb were overexpressed in degenerative fibers. These results suggest that oxidative stress is associated with Mb expression specifically in mitochondrial diseases. The antioxidant enzymes seem to be upregulated to protect against muscle damage in nonatrophic RRFs. However, the Mb-mediated oxidative damage may become more extensive and result in further mitochondrial dysfunction and progressive atrophy of RRF with impaired upregulation of Mb.
Emiko Tohjima, Daisuke Inoue, Nobuchika Yamamoto, Shinsuke Kido, Yuji Ito, Shuji Kato, Yasuhiro Takeuchi, Seiji Fukumoto and Toshio Matsumoto : Decreased AP-1 activity and interleukin-11 expression by bone marrow stromal cells may be associated with impaired bone formation in aged mice, Journal of Bone and Mineral Research, Vol.18, No.8, 1461-1470, 2003.
(Summary)
Expression of an osteogenic cytokine, IL-11, is decreased in SAMP6. We show here that IL-11 transcription largely depends on AP-1 transcription factors, activities of which are decreased in SAMP6 as well as aged ICR mice. Therefore, diminished AP-1 activity and the resultant decline in IL-11 expression may play a role in impaired bone formation in the aged. Evidence suggests that impaired osteoblastogenesis contributes to aging-associated osteopenia. The P6 strain of senescence-accelerated mice (SAM) is an animal model of senile osteoporosis, which exhibits low bone mass caused by impaired bone formation. Bone marrow stromal cells from SAMP6 show decreased osteoblastogenesis and increased adipogenesis. We previously demonstrated that these abnormalities of SAMP6 stromal cells may be attributed to decreased expression of interleukin (IL)-11. In this study, we attempted to determine the molecular mechanism of decreased IL-11 expression by SAMP6 stromal cells by cloning and analyzing the mouse IL-11 gene promoter. We found that two tandem activating protein-1 (AP-1) sites that reside immediately upstream of TATA box play critical roles in IL-11 gene transcription. Gel shift analysis showed that binding activity to the IL-11 AP-1 sites was reduced in SAMP6 stromal cell nuclear extracts. Among multiple components of AP-1 transcription factors, Jun D binding was particularly decreased. Furthermore, decreased Jun D binding and IL-11 expression by stromal cells was also observed in aged mice of the ICR strain. Therefore, decreased AP-1 activity and a resultant decline in IL-11 expression by bone marrow stromal cells may play a role in impaired bone formation in the aged.
Mitsunori Fujimura, Masashi Akaike, Midori Kato, Nobuyuki Takamori, Masahiro Abe, Takeshi Nishiuchi, Hiroyuki Azuma and Toshio Matsumoto : Aggressive antiplatelet therapy before coronary stent implantation in acute coronary syndrome with essential thrombocythemia--a case report, Angiology, Vol.54, No.4, 485-490, 2003.
(Summary)
A 52-year-old man was admitted to the hospital because of unstable angina pectoris. Coronary angiography revealed severe stenosis at a proximal site of the left anterior descending artery. Essential thrombocythemia (ET) was diagnosed on the basis of findings of marked thrombocytosis (106 x 10(4)/microL) and an increased number of immature megakaryocytes in the bone marrow. Because hyperaggregability of platelets was demonstrated by an ex vivo platelet aggregation assay and by elevated plasma levels of beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4), antiplatelet therapy with aspirin and ticlopidine and cytoreduction therapy with hydroxyurea were started. This combination treatment resulted in a decrease in the platelet count to less than 60 x 10(4)/microL and decreases in plasma levels of both beta-TG and PF4 to almost normal values. Percutaneous coronary angioplasty and stenting were then performed successfully without thrombotic complications. These findings suggest that combination therapy with antiplatelet and cytoreduction agents before catheter intervention is useful for the prevention of thrombotic complications in patients with acute coronary syndrome associated with essential thrombocythemia.
Nami Inoue, Makoto Kunishige, Sumiko Yoshida, Yasushi Oshima, Yoshiaki Ohnishi, Yasuhiro Kuroda, Atsuko Asano, Hiide Yoshino, Toshio Matsumoto and Takao Mitsui : Dissociation between titer of anti-ganglioside antibody and severity of symptoms in a case of Guillain-Barre syndrome with treatment-related fluctuation, Journal of the Neurological Sciences, Vol.210, No.1-2, 105-108, 2003.
(Summary)
Since plasma exchange (PE) and intravenous immunoglobulin (i.v.Ig) have been widely used in treatment for Guillain-Barré syndrome (GBS), early relapse and treatment-related fluctuation have been a potential problem, but little is known about the mechanism of relapse and fluctuation. We describe a patient who had GBS with treatment-related fluctuation. A 37-year-old Japanese man exhibited acute distal-dominant weakness in upper limbs after upper respiratory infection. His cranial nerve system was normal and muscle weakness was limited to upper limbs. Anti-GT1a IgG was strongly positive and anti-GQ1b IgG was also detected in his serum. Muscle weakness responded well to double-filtration plasmapheresis (DFPP) followed by i.v.Ig, but relapsed 45 days after the initial treatment. Although repeated treatments were effective, the patient showed additional minor deterioration twice. Motor nerve conduction velocities (MCVs) corresponded to the muscle weakness, but elevated level of cerebrospinal fluid (CSF) protein remained and anti-ganglioside antibody titers steadily decreased throughout the clinical course. These findings indicate that the clinical fluctuation was not due to changes in the production of anti-ganglioside antibodies but presumably to the transient beneficial effects of DFPP/i.v.Ig and the outlasting inflammatory response in peripheral nerves.
T Shigekiyo, O Fujino, Y Kanagawa and Toshio Matsumoto : Prekallikrein (PK) Tokushima: PK deficiency caused by a Gly401-->Glu mutation, Journal of Thrombosis and Haemostasis, Vol.1, No.6, 1314-1316, 2003.
(Keyword)
DNA Mutational Analysis / Humans / Male / Middle Aged / Mutation, Missense / Pedigree / Prekallikrein
Shinsuke Kido, Daisuke Inoue, Kenji Hiura, Wilde Javier, Yuji Ito and Toshio Matsumoto : Expression of RANK is dependent upon differentiation into the macrophage/osteoclast lineage: induction by 1alpha,25-dihydroxyvitamin D3 and TPA in a human myelomonocytic cell line, HL60, Bone, Vol.32, No.6, 621-629, 2003.
(Summary)
Receptor activator of nuclear factor (RANK) is a member of the tumor necrosis factor receptor superfamily indispensable for osteoclast differentiation. However, little is known about the regulatory mechanism of RANK expression. In the present study, RANK expression during macrophage/osteoclast differentiation was investigated using a human myelomonocytic cell line, HL60, capable of differentiating into mature osteoclasts under appropriate conditions. RANK mRNA expression was barely detectable in growing HL60 cells. We found that treatment with 1alpha,25-dihydroxyvitamin D(3) and TPA resulted in an apparent induction of RANK mRNA and protein in association with differentiation into the macrophage/osteoclast lineage. Induction of RANK was time and dose dependent and lineage specific. Moreover, RANK induction was blocked by an RNA polymerase II inhibitor, suggesting an involvement of a transcriptional mechanism. The induced RANK was functional as it was able to bind RANK ligand and activate NF-kappaB. In the induced HL60 cells expressing both c-Fms and RANK, RANK mRNA expression was further enhanced by RANKL, but not by macrophage colony-stimulating factor. These results suggest a positive feedback regulation of RANK expression by its own intracellular signaling. The in vitro system described here may be a useful model to elucidate the regulatory mechanism of RANK expression and its role in human osteoclastogenesis.
Soichi Honda, Chisato Kosugi, Shozo Yamada, Toshiaki Sano, Toshio Matsumoto, Mitsuo Itakura and Katsuhiko Yoshimoto : Human Pituitary Adenomas Infrequently Contain Inactivation of Retinoblastoma 1 Gene and Activation of Cyclin Dependent Kinase 4 Gene., Endocrine Journal, Vol.50, No.3, 309-318, 2003.
(Summary)
Components of cyclinD1/cyclin-dependent kinase 4 (CDK4)/p16INK4a/pRb pathway are the frequent target of many tumor types. We examined the role of retinoblastoma susceptibility gene (RB1) and the CDK4 gene in human pituitary tumorigenesis. For the RB1 gene, pRb expression and loss of heterozygosity (LOH) on 13q in pituitary adenomas were analysed. Immunostaining of pRb revealed lack of expression in 1 of 29 pituitary adenomas. In 4 of 31 pituitary adenomas, allelic imbalances including LOH of RB1 on 13q14 were detected. Three of 4 pituitary adenomas, in which one adenoma lacked pRb expression, had a common LOH region at least from D13S219 on 13q12.3-q13 to D13S265 on 13q31-32. Interphase fluorescence in situ hybridization with a probe of RB1 showed 2 copies of RB1 gene suggesting that mitotic recombination events, not deletion or chromosome loss, led to LOH in the 3 pituitary adenomas analyzed. All 27 exons, intron-exon boundaries, and essential promoter region of RB1 gene were then sequenced in genomic DNA from 4 pituitary adenomas with allelic imbalance on 13q14 including one adenoma without pRb expression and 3 adenomas with pRb expression. Any somatic mutations, insertions, or microdeletions in the RB1 gene were not detected in 4 pituitary adenomas. Methylation sensitive (MS)-polymerase chain reaction (PCR) and bisulfite sequencing analysis revealed hypomethylated status of CpG islands in the promoter region of the RB1 genes of 4 pituitary adenomas. In addition, activating mutations of CDK4 gene, which is a component of cyclinD1/CDK4/p16INK4a/pRb pathway, were not detected in 31 pituitary adenomas. Based on these results, it is concluded that somatic mutations of the RB1 gene or CDK4 gene do not appear to play a major role in pituitary tumorigenesis. This supports the presence of potential tumor suppressor gene(s) on 13q12.3-q13 to 13q31-32 in pituitary adenomas.
Takahiko Iuchi, Masashi Akaike, Takao Mitsui, Yasushi Ohshima, Yasumi Shintani, Hiroyuki Azuma and Toshio Matsumoto : Glucocorticoid Excess Induces Superoxide Production in Vascular Endothelial Cells and Elicits Vascular Endothelial Dysfunction, Circulation Research, Vol.92, No.1, 81-87, 2003.
(Summary)
Glucocorticoid (GC) excess often elicits serious adverse effects on the vascular system, such as hypertension and atherosclerosis, and effective prophylaxis for these complications is limited. We sought to reveal the mechanism underlying GC-induced vascular complications. Responses in forearm blood flow to reactive hyperemia in 20 GC-treated patients were significantly decreased to 43+/-8.9% (mean+/-SEM) from the values obtained before GC therapy (130+/-14%). An administration of vitamin C almost normalized blood flow responses. In human umbilical vein endothelial cells (HUVECs), production of hydrogen peroxide was increased up to 166.5+/-3.3% of control values by 10(-7) mol/L dexamethasone (DEX) treatment (P<0.01). Concomitant with DEX-induced hydrogen peroxide production, intracellular amounts of peroxynitrite significantly increased and those of nitric oxide (NO) decreased, respectively (P<0.01). Immunoblotting analysis using anti-nitrotyrosine antibody showed that peroxynitrite formation was increased in DEX-treated HUVECs. Using inhibitors against metabolic pathways for generation of reactive oxygen species (ROS), we identified that the major production sources of ROS by DEX treatment were mitochondrial electron transport chain, NAD(P)H oxidase, and xanthine oxidase. These findings suggest that GC excess causes overproduction of ROS and thereby perturbs NO availability in the vascular endothelium, leading to vascular complications in patients with GC excess.
(Keyword)
Glucocorticoid / reactive oxygen species / nitric oxide / vascular endothelial function
Yasuhiro Takeuchi, Sumiyo Watanabe, Genichiro Ishii, Shu Takeda, Konosuke Nakayama, Seiji Fukumoto, Yasuyuki Kaneta, Daisuke Inoue, Toshio Matsumoto, Kenichi Harigaya and Toshiro Fujita : Interleukin-11 as a Stimulatory Factor for Bone Formation Prevents Bone Loss with Advancing Age in Mice*, The Journal of Biological Chemistry, Vol.277, No.50, 49011-49018, 2002.
(Summary)
Cytokines in interleukin (IL)-11 subfamily participate in the regulation of bone cell proliferation and differentiation. We report here positive effects of IL-11 on osteoblasts and bone formation. Overexpression of human IL-11 gene in transgenic mice resulted in the stimulation of bone formation to increase cortical thickness and strength of long bones, and in the prevention of cortical bone loss with advancing age. Bone resorption and osteoclastogenesis were not affected in IL-11 transgenic mice. In experiments in vitro, IL-11 stimulated transcription of the target gene for bone morphogenetic protein (BMP) via STAT3, leading to osteoblastic differentiation in the presence of BMP-2, but inhibited adipogenesis in bone marrow stromal cells. These results indicate that IL-11 is a stimulatory factor for osteoblastogenesis and bone formation to conserve cortical bone, possibly by enhancing BMP actions in bone. IL-11 may be a new therapeutic target for senile osteoporosis.
(Keyword)
aging / Animals / Base Sequence / Bone Development / Bone Marrow Cells / Bone Morphogenetic Proteins / Bone Resorption / Cells, Cultured / Chromans / DNA Primers / Humans / Interleukin-11 / Male / Mice / Mice, Transgenic / Recombinant Proteins / Thiazoles / Thiazolidinediones / Transcription, Genetic
Itsuro Endo, Takao Mitsui and Toshio Matsumoto : Diurnal fluctuation of edema synchronized with plasma VEGF concentration in patient with POEMS syndrome., Internal Medicine, Vol.41, No.12, 1196-1198, 2002.
(Summary)
A case of POEMS syndrome in a 49-year-old Japanese woman is reported. The patient exhibited prominent edema in her legs at night, but her edema usually improved by the following morning. The plasma concentrations of VEGF in the patient showed diurnal fluctuations; plasma VEGF levels peaked at night and decreased in the daytime. Immunocytochemical study demonstrated the expression of VEGF in IgA- and λ-positive plasma cells in bone marrow. The results indicate that VEGF was produced at least by plasma cells and that VEGF production was regulated by circadian rhythm in synchronization with the development of edema.(Internal Medicine 41: 1196-1198, 2002)
Y Oshima, Takao Mitsui, H Yoshino, I Endo, M Kunishige, A Asano and Toshio Matsumoto : Central motor conduction in patients with anti-ganglioside antibody associated neuropathy syndromes and hyperreflexia, Journal of Neurology, Neurosurgery, and Psychiatry, Vol.73, No.5, 568-573, 2002.
(Summary)
Several serum antibodies against gangliosides are diagnostically important, particularly in Guillain-Barré syndrome (GBS), Miller Fisher syndrome (MFS), and multifocal motor neuropathy (MMN). Although hyperreflexia is an atypical symptom in these disorders, it has been found in some patients with GBS, MFS, and MMN. The aim of the study was to determine whether hyperreflexia corresponds to corticospinal tract dysfunction in these patients. The study examined central and peripheral motor conduction in patients with hyperreflexia who exhibited acute paralysis (group 1, n=5), acute ataxia and ophthalmoplegia (group 2, n=7), or chronic paralysis with conduction block (group 3, n=2). The clinical symptoms are similar to those in patients with GBS, MFS, and MMN, respectively, and serum anti-ganglioside antibodies were found to be positive in all patients. Using magnetic and electrical stimulation techniques, central and peripheral motor conduction were compared in patients in groups 1, 2, and 3 and patients with GBS (n=7), MFS (n=8), and MMN (n=6). Central motor conduction times (CMCTs) in patients in groups 1, 2, and 3 were significantly delayed compared with those in patients with GBS, MFS, and MMN (p<0.01, p<0.05, p<0.05, respectively), and the delayed CMCTs significantly improved in the recovery periods (p<0.01, p<0.01, p<0.05, respectively). However, motor conduction velocity, compound muscle action potential, and F wave conduction velocity were not significantly different between the patients. These findings indicate that corticospinal tract is functionally involved in patients with anti-ganglioside antibody associated neuropathy syndromes and hyperreflexia
(Keyword)
Guillain-Barré syndrome / Miller Fisher syndrome / multifocal motor neuropathy / central motor conduction time
E Fukunaga, M Kunishige, Takao Mitsui, I Endo, Y Oshima, Y Ohnishi, Y Kuroda, S Hara and Toshio Matsumoto : Severe dermatomyositis with rhabdomyolysis and paralytic ileus: a case successfully treated with plasmapheresis and intravenous immunoglobulin, European Journal of Neurology, Vol.9, No.6, 697-698, 2002.
Masahiro Abe, Kenji Hiura, Javier Wilde, Keiji Moriyama, Toshihiro Hashimoto, Shuji Ozaki, Shingo Wakatsuki, Masaaki Kosaka, Shinsuke Kido, Daisuke Inoue and Toshio Matsumoto : Role for macrophage inflammatory protein (MIP)-1α and MIP-1β in the development of osteolytic lesions in multiple myeloma, Blood, Vol.100, No.6, 2195-2202, 2002.
(Summary)
Multiple myeloma (MM) cells cause devastating bone destruction by activating osteoclasts in the bone marrow milieu. However, the mechanism of enhanced bone resorption in patients with myeloma is poorly understood. In the present study, we investigated a role of C-C chemokines, macrophage inflammatory protein (MIP)-1alpha and MIP-1beta, in MM cell-induced osteolysis. These chemokines were produced and secreted by a majority of MM cell lines as well as primary MM cells from patients. Secretion of MIP-1alpha and MIP-1beta correlated well with the ability of myeloma cells to enhance osteoclastic bone resorption both in vitro and in vivo as well as in MM patients. In osteoclastogenic cultures of rabbit bone cells, cocultures with myeloma cells as well as addition of myeloma cell-conditioned media enhanced both formation of osteoclastlike cells and resorption pits to an extent comparable to the effect of recombinant MIP-1alpha and MIP-1beta. Importantly, these effects were mostly reversed by neutralizing antibodies against MIP-1alpha and MIP-1beta, or their cognate receptor, CCR5, suggesting critical roles of these chemokines. We also demonstrated that stromal cells express CCR5 and that recombinant MIP-1alpha and MIP-1beta induce expression of receptor activator of nuclear factor-kappaB (RANK) ligand by stromal cells, thereby stimulating osteoclast differentiation of preosteoclastic cells. These results suggest that MIP-1alpha and MIP-1beta may be major osteoclast-activating factors produced by MM cells.
Masashi Akaike, Hiroyuki Azuma, Ayako Kagawa, Kazuya Matsumoto, Ikuro Hayashi, Katsuya Tamura, Takeshi Nishiuchi, Takahiko Iuchi, Nobuyuki Takamori, Ken-ichi Aihara, Tomonori Yoshida, Yasuhiko Kanagawa and Toshio Matsumoto : Effect of Aspirin Treatment on Serum Concentrations of Lipoprotein(a) in Patients with Atherosclerotic Diseases, Clinical Chemistry, Vol.48, No.9, 1454-1459, 2002.
(Summary)
Increased serum lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerosis. We previously reported that aspirin reduced Lp(a) production by cultured hepatocytes via the reduction of apolipoprotein(a) [apo(a)] gene transcription. We evaluated both the effect of aspirin treatment (81 mg/day) on serum Lp(a) concentrations and the correlation between the degree of reduction in serum Lp(a) and the type of apo(a) isoform in 70 patients with coronary artery disease or cerebral infarction. Aspirin lowered serum Lp(a) concentrations to approximately 80% of the baseline values in patients with high Lp(a) concentrations (>300 mg/L). The percentage of decrease in serum Lp(a) was larger in patients with high Lp(a) than in patients with low Lp(a) (<300 mg/L), irrespective of apo(a) isoform size. The decreases in serum Lp(a) in high Lp(a) patients with both the high-molecular-weight and the low-molecular-weight isoforms were positively correlated with the baseline Lp(a) concentrations. Because the secretory efficiencies of apo(a) in the same isoform are likely to be similar, the difference in serum Lp(a) concentrations in patients having the same apo(a) isoform depends on the transcriptional activity of the apo(a) gene. These findings suggest that aspirin decreases serum Lp(a) concentrations via a decrease in apo(a) gene transcription more effectively in patients with high transcriptional activity of this gene.
Takao Mitsui, Yoshifumi Umaki, Masakazu Nagasawa, Masashi Akaike, Kenji Aki, Hiroyuki Azuma, Shuji Ozaki, Masaaki Odomi and Toshio Matsumoto : Mitochondrial damage in patients with long-term corticosteroid therapy: development of oculoskeletal symptoms similar to mitochondrial disease, Acta Neuropathologica, Vol.104, No.3, 260-266, 2002.
(Summary)
Two patients with long-term corticosteroid administration sporadically developed limb muscle wasting followed by ophthalmoplegia, and the skeletal muscle pathology revealed ragged-red fibers (RRFs) with abnormal mitochondria, in addition to the findings of corticosteroid myopathy. The oculoskeletal symptoms of the present cases resemble those of chronic progressive external ophthalmoplegia, a type of mitochondrial disease. The ocular muscles have more RRFs than limb muscles, and large multiple deletions of mitochondrial DNA was detected in ocular and limb muscles of the two patients by PCR but not by Southern blotting. Immunohistochemistry demonstrated that 8-hydroxy-deoxyguanosine (8-OH-dG) and 4-hydroxy-2-nonenal were intensely stained in skeletal muscles of these patients particularly in RRFs. High-performance liquid chromatography with electrochemical detection analysis revealed an increase in 8-OH-dG from mitochondrial DNA. These findings may suggest that long-term corticosteroid administration potentially induces oxidative stress-mediated mitochondrial damage, resulting in the development of the oculoskeletal symptoms in some patients.
Masahiro Abe, Yasumi Shintani, Yuzuru Eto, Kazuyo Harada, Masaaki Kosaka and Toshio Matsumoto : Potent induction of activin A secretion from monocytes and bone marrow stromal fibroblasts by cognate interaction with activated T cells, Journal of Leukocyte Biology, Vol.72, No.2, 347-352, 2002.
(Summary)
Activin A is a multifunctional cytokine essential for cell differentiation and apoptosis including erythroid cell differentiation in the bone marrow. In addition, activin A is induced by inflammation and exerts anti-inflammatory effects. However, the mechanism of activin A induction is still unclear, especially by inflammatory processes. Here we show that activin A secretion from monocytes and bone marrow stromal fibroblasts, its major sources in the bone marrow, is markedly enhanced by cognate interaction with activated T cells. This process is mediated by CD40/CD40 ligand interaction as well as concomitantly secreted T cell-derived cytokines, granulocyte macrophage-colony stimulating factor, and interferon-gamma. Furthermore, stromal fibroblasts as well as monocytes provide a costimulatory signal to anti-CD3-treated T cells via CD80 and CD86 to maintain the enhanced activin A production. These findings suggest that activin A is potently induced in the bone marrow and may play a role in the suppression of inflammatory or immune processes.
(Keyword)
CD40 / CD28 / costimulation / GM-CSF / IFN-γ
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● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 12149426
Corticosteroid myopathy is a major clinical problem in patients undergoing chronic corticosteroid treatment and shows insidious and progressive muscle atrophy in proximal limbs. Although several mechanisms underlying the pathophysiology of muscle injury have been postulated, precise pathogenesis is still not clear. We evaluated the mitochondrial functions in patients receiving corticosteroids compared with those in healthy controls or patients not receiving corticosteroids. The serum levels and total production of lactate were investigated by an aerobic exercise test using a bicycle ergometer. Mitochondrial respiratory activities and oxidative damage in biopsied skeletal muscles were also studied. The results of aerobic exercise tests revealed a significant overproduction of lactate in patients treated with corticosteroids ( p < 0.005), which was positively correlated with total corticosteroid doses administered ( p < 0.0001). In these patients, mitochondrial enzyme activity in complex I was significantly decreased ( p < 0.05) and oxidative damage of biopsied skeletal muscle was remarkable both in mitochondrial and nuclear DNAs ( p < 0.001). The results suggest that chronic corticosteroid administration induces mitochondrial dysfunction and oxidative damage in skeletal muscles, which may be the pathogenesis, at least in part, of corticosteroid-induced myopathy.
Toshio Matsumoto, N Nagata, N Horikoshi, I Adachi and Y Ohashi : Comparative study of incadronate and elcatonin in patients with malignancy-associated hypercalcaemia, The Journal of International Medical Research, Vol.30, No.3, 230-243, 2002.
(Summary)
The clinical usefulness of incadronate was compared with elcatonin in 26 patients with malignancy-associated hypercalcaemia. Data from 21 and 24 patients could be used to assess efficacy and safety, respectively. Eleven patients were given a single 10-mg intravenous infusion of incadronate and 10 received twice-daily intramuscular injections of 40 IU of elcatonin for 7 consecutive days. After treatment, corrected serum calcium levels decreased significantly in both groups. The anti-hypercalcaemic effect of elcatonin was characterized by its rapid onset, with serum calcium levels reduced 1 day after administration. In contrast, the anti-hypercalcaemic effect of incadronate was more sustained but only became apparent a few days after infusion. Evaluation of symptoms revealed significantly greater improvement rates in the incadronate group compared with the elcatonin group. Adverse drug reactions were observed in three patients in the incadronate group, i.e. mild and transient fever in two cases and exacerbation of disturbance of consciousness in one case. These findings suggest that incadronate produces more marked and sustained hypocalcaemic effects than elcatonin, and that co-administration of these two drugs may yield both rapid and sustained control of malignancy-associated hypercalcaemia.
Rika Kuriwaka, Takao Mitsui, Soichiro Fujiwara, Yoshihiko Nishida and Toshio Matsumoto : Loss of postural reflexes in long-term occupational solvent exposure, European Neurology, Vol.47, No.2, 85-87, 2002.
(Summary)
Inhalation of organic solvents has long been known to damage various nervous systems, including cerebellum, brainstem, and pyramidal tract. However, little is known about the damage of the dopaminergic system. We report two patients with occupational long-term solvent exposure who developed postural instability without other features of parkinsonism. The concentration of HVA in CSF was decreased and the retropulsion was dramatically improved after the administration of levodopa. These findings indicate that the nigrostriatal dopaminergic neurons were disturbed by chronic solvent exposure, resulting in the loss of postural reflexes.
Yoshifumi Umaki, Takao Mitsui, Itsuro Endo, Masashi Akaike and Toshio Matsumoto : Apoptosis-related changes in skeletal muscles of patients with mitochondrial diseases, Acta Neuropathologica, Vol.103, No.2, 163-170, 2002.
(Summary)
Much interest has recently been shown in apoptosis-mediated roles in the pathophysiology of mitochondrial diseases, because mitochondrial defects are implicated in a wide variety of degenerative diseases. We investigated whether apoptotic events occurred in skeletal muscles of patients with mitochondrial diseases, including chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayer syndrome (KSS), and mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). In a immunohistochemical study, stainings for 8-hydroxy-deoxyguanosine (8-OH-dG), 4-hydroxy-nonenal (4-HNE), Mn-SOD, Bcl-2, cytochrome c, DNase I and Bcl-x L showed a pronounced granular distribution in the cytochrome c oxidase (COX)-negative ragged-red fibers (RRFs). On the other hand, the signals for Bax, p53, Fas and caspase 3 were not obviously increased in RRFs. In situ labeling of DNA breaks demonstrated preferential signals not only in myonuclei but also in subsarcolemmal regions of RRFs, indicating that mitochondrial as well as myonuclear DNA is fragmented in RRFs. An immunoblotting study demonstrated that cytochrome c was increased in the cytosol of diseased muscles and that DNase I was increased in mitochondria, compared to that of normal muscles. No difference was observed between protein bands at 20 kDa corresponding to caspase 3 in diseased and normal muscles. These findings demonstrate that these mitochondrial diseases harbor unique apoptosis-related changes that differ from caspase 3-dependent apoptosis. It is thought that these changes are induced by superoxide overproduction and cytochrome c release resulting from an inherent mitochondrial defect and that the events are associated with DNase I activation.
(Keyword)
apoptosis / Reactive oxygen species / Cytochrome c release / caspase / Deoxyribonuclease
Naoko Yagishita, Yoko Yamamoto, Tatsuya Yoshizawa, Keisuke Sekine, Yoshikatsu Uematsu, Hisashi Murayama, Yumiko Nagai, Wojciech Krezel, Pierre Chambon, Toshio Matsumoto and Shigeaki Kato : Aberrant Growth Plate Development in VDR/RXR Double Null Mutant Mice, Endocrinology, Vol.142, No.12, 5332-5341, 2001.
(Summary)
VDR forms heterodimers with one of three RXRs, RXR alpha, RXR beta, and RXR gamma, and it is thought that RXR ligands can also modulate the trans-activation function of VDR/RXR heterodimers. In the present study we generated VDR/RXR gamma double null mutant mice to examine the convergent actions of vitamin D and vitamin A signaling and to explore the possibility of a functionally redundant VDR. Although RXR gamma(-/-) mice exhibited no overt abnormalities, VDR(-/-)/RXR gamma(-/-) mice appeared similar to VDR(-/-) mice, showing features typical of vitamin D-dependent rickets type II, including growth retardation, impaired bone formation, hypocalcemia, and alopecia. However, compared to VDR(-/-) mice, growth plate development in VDR(-/-)/RXR gamma(-/-) mutant mice was more severely impaired. Normalizing mineral ion homeostasis through dietary supplementation with high calcium and phosphorous effectively prevented rachitic abnormalities, except for disarranged growth plates in VDR(-/-)/RXR gamma(-/-) mutant mice, and alopecia in both VDR(-/-) and VDR(-/-)/RXR gamma(-/-) mutant mice. Histological analysis of VDR(-/-)/RXR gamma(-/-) growth plates revealed that development of the hypertrophic chondrocytes was selectively impaired. Thus, our findings indicated that the combined actions of VDR- and RXR gamma-mediated signals are essential for the normal development of growth plate chondrocytes, and raised the possibility that a functionally redundant VDR is present on chondrocytes as a heterodimer with RXR gamma.
Masahiro Abe, Yasumi Shintani, Yuzuru Eto, Kazuyo Harada, Yuichi Fujinaka, Masaaki Kosaka and Toshio Matsumoto : Interleukin-1 β enhances and interferon-γ suppresses activin A actions by reciprocally regulating activin A and follistatin secretion from bone marrow stromal fibroblasts, Clinical and Experimental Immunology, Vol.126, No.1, 64-68, 2001.
(Summary)
Activin A is a multi-functional cytokine with a potent stimulation on erythroid cell differentiation in the bone marrow. The actions of activin A are determined by a balance of the levels of activin A and its inhibitor, follistatin (FS). However, the regulation of its actions in the bone marrow has been unclear. Here we show that bone marrow-derived stromal fibroblasts are the major source of activin A and FS in the bone marrow, and that the production of activin A is enhanced by interleukin-1beta (IL-1beta) and lipopolysaccharide (LPS), whereas interferon-gamma (IFN-gamma) inhibits the secretion of activin A by stromal fibroblasts. Concomitantly, IL-1beta as well as LPS inhibits and IFN-gamma stimulates FS secretion from stromal fibroblasts. Thus, these cytokines potently regulate activin A actions by reciprocal modulation of activin A and FS secretion from stromal fibroblasts. Because activin A exhibits anti-inflammatory effects in various tissues, up-regulation of activin A actions by IL-1beta and endotoxin in the bone marrow may play a protective role against inflammatory processes as well as anaemia. The present results also suggest that the inhibitory effect of IFN-gamma on erythropoiesis is mediated at least in part by a suppression of activin A actions in bone marrow.
Y Kuroda, Takao Mitsui, Masashi Akaike, Hiroyuki Azuma and Toshio Matsumoto : Homozygous deletion mutation of the parkin gene in patients with atypical parkinsonism, Journal of Neurology, Neurosurgery, and Psychiatry, Vol.71, No.2, 231-234, 2001.
(Summary)
Autosomal recessive juvenile parkinsonism (AR-JP) is characterised by homogenous clinical features and selective degeneration of nigral neurons. Recent progress in molecular genetic analyses of AR-JP has led to the identification of a novel ubiquitin-like protein, parkin, whose precise function still remains to be elucidated. Two unrelated Japanese families had levodopa unresponsive parkinsonism complicated with cerebellar and pyramidal tract dysfunction. Genetic analysis of the parkin gene and mRNA in both families disclosed identical mutations with large deletions extending from exons 3 to 4. These results suggest that the parkin protein possesses an important function not only in the substantia nigra but also in extranigral neurons of the CNS and that the phenotype of multiple system dysfunction can also be a complication in patients with AR-JP due to variations in sites of or changes in functions by parkin mutation.
(Keyword)
AR-JP / parkin / multiple system degeneration / deletion mutation
Toshihiro Hashimoto, Makoto Takishita, Masaki Kosaka, Toshiaki Sano and Toshio Matsumoto : Superantigens and autoantigens may be involved in the pathogenesis of gastric mucosa-associated lymphoid tissue lymphoma, International Journal of Hematology, Vol.74, No.2, 197-204, 2001.
(Summary)
To clarify the origin of tumor cells and the possible role of antigens in the pathogenesis of mucosa-associated lymphoid tissue lymphoma (MALTL) of the stomach, we analyzed the DNA sequences of the immunoglobulin (Ig) variable region gene from tumor cells of 4 patients with low-grade and 2 patients with high-grade MALTL associated with Helicobacter pylori infection. There were few somatic mutations in the Ig variable region gene, but intraclonal variations were observed in 2 of the 4 low-grade MALTL cases. In the remaining 2 low-grade MALTL and 1 of the 2 high-grade MALTL cases, somatic mutations and intraclonal variations were evident. In contrast, somatic mutations in the Ig variable region gene were prominent, but intraclonal variation was absent in the other high-grade MALTL cases. The deduced amino acid sequences of the antigen-binding fragments (Fab) from 2 MALTL cases revealed homology with anti-thyroglobulin antibodies, 3 MALTL cases with lupus anti-DNA antibodies, and 1 MALTL case with a rheumatoid factor. Furthermore, the heavy-chain variable region 3 (V(H)3) family genes were used in 5 of the 6 MALTL cases and had conserved amino acid residues for binding to staphylococcal protein A (SpA), a superantigen of B cells. Considering that another superantigen, protein Fv, competes for binding to Fab with SpA and has been shown to play a major role in immune defenses against gut pathogens, SpA and possibly protein Fv may contribute to the development of MALTL. Thus, these observations suggest that most gastric MALTLs arise from memory B cells that are preliminarily activated by superantigens and autoantigens.
(Keyword)
mucosa-associated lymphoid tissue lymphoma / immunoglobulin gene / staphylococcal protein A / protein Fv / Superantigen
Masahiro Abe, Y Shintani, Y Eto, K Harada, Y Fujinaka, M Kosaka and Toshio Matsumoto : Interleukin 1β enhances and interferon-γ suppresses activin A actions by reciprocally regulating activin A and follistatin secretion from bone marrow stromal fibroblasts, Clinical and Experimental Immunology, Vol.126, 64-68, 2001.
Mieko Saika, Daisuke Inoue, Shinsuke Kido and Toshio Matsumoto : 17β-Estradiol stimulates expression of osteoprotegerin by a mouse stromal cell line, ST-2, via estrogen receptor-α, Endocrinology, Vol.142, No.6, 2205-2212, 2001.
(Summary)
Osteoprotegerin (OPG) is a recently identified member of the tumor necrosis factor (TNF) receptor superfamily that regulates bone mass through an inhibitory action on osteoclast differentiation and function. To determine its potential roles of OPG in pathological changes in bone metabolism caused by estrogen deficiency, we investigated effects of estrogen on OPG expression by a mouse stromal cell line, ST-2, in vitro. Treatment of ST-2 cells with 17beta-E(2) resulted in up-regulation of OPG expression at both the messenger RNA and protein levels. The effect was time and dose dependent and steroid specific. The stimulatory action of 17beta-E(2) on OPG expression appeared to be mediated by the estrogen receptor-alpha (ERalpha) subtype because stable overexpression of ERalpha, but not of ERbeta, enhanced the OPG induction by 17beta-E(2). Moreover, estrogen withdrawal after 5-day pretreatment, mimicking the event occurring in vivo at menopause, dramatically diminished the expression of OPG. These findings suggest that down-regulation of OPG after estrogen withdrawal contributes to the enhanced osteoclastic bone resorption and bone loss after menopause by enhancing RANK ligand-RANK system that lies downstream of a large number of bone-resorbing cytokines.
Ken-ichi Aihara, Hiroyuki Azuma, Yasumasa Ikeda, Masashi Akaike, Masahiro Abe, Takashi Sugihara and Toshio Matsumoto : Successful combination therapy--flunarizine,pentoxifylline, and cholestyramine--for spur cell anemia, International Journal of Hematology, Vol.73, No.3, 351-355, 2001.
(Summary)
Spur cell anemia, a hemolytic anemia observed in patients with alcoholic cirrhosis, is characterized by unusual erythrocyte morphology and an increased ratio of free cholesterol to phospholipid in the erythrocyte membrane. The prognosis of spur cell anemia is usually extremely poor, however, we describe here a patient with spur cell anemia who was successfully treated with combination therapy consisting of flunarizine, pentoxifylline, and cholestyramine. Initial therapy with flunarizine alone for 6 weeks did not significantly decrease the number of spur cells on peripheral blood smears. So pentoxifylline was added to the regimen. The patient recovered from the anemia, showed remarkable improvement with regard to the hyperbilirubinemia, and the changes were accompanied by a significant decrease in the number of spur cells in peripheral blood smears. To correct the hypercholesterolemia, cholestyramine was added to the regimen, which resulted in a reduction in the serum level of free cholesterol and an increase in the molar ratio of free cholesterol to phospholipid in erythrocyte membrane. However, 6 months later a skin eruption developed that was considered an adverse reaction to the drugs, so the flunarizine and pentoxifylline were discontinued. With cholestyramine therapy alone, the remission of spur cell anemia was maintained for more than 11 months. These observations suggest that non-invasive combination therapy with flunarizine, pentoxifylline, and cholestyramine is effective and valuable in the treatment of patients with spur cell anemia.
A Nakano, Takao Mitsui, I Endo, Y Takeda, Shuji Ozaki and Toshio Matsumoto : Solitary plasmacytoma with VEGF overproduction: report of a patient with polyneuropathy, Neurology, Vol.56, No.6, 818-819, 2001.
Yasuhiko Kanagawa, Toshio Shigekiyo, Ken-ichi Aihara, Masashi Akaike, Hiroyuki Azuma and Toshio Matsumoto : Molecular mechanism of type I congenital heparin cofactor (HC) II deficiency caused by a missense mutation at reactive P2 site: HC II Tokushima, Thrombosis and Haemostasis, Vol.85, No.1, 101-107, 2001.
(Summary)
We found a 66-year-old Japanese patient with type I congenital heparin cofactor (HC) II deficiency manifesting multiple atherosclerotic lesions. To investigate the molecular pathogenesis of our patient, we performed sequencing analysis and expressed recombinant human wild-type and mutant HC II molecules in COS-1 and CHO-K1 cells. Sequencing analysis following amplification of each of all 5 exons and its flanking region showed a single C to T transition at nucleotide position 12,854 in exon 5, which changed a Pro443 codon (CCG) to Leu codon (CTG). Because this mutation generates a new Bhv I site, the Bbv I digestion pattern of the PCR-amplified exon 5 fragments from each family member was analyzed. In all cases, the patterns were consistent with the activities and antigen levels of plasma HC I1 in those members. Transient transfection, metabolic labeling and pulse-chase experiments followed by immunoprecipitation analysis showed that the recombinant mutant HC II molecules were secreted from COS-1 cells in reduced amounts compared with the wild-type, and that an enhanced intracellular association of the mutant molecules with a chaperone, GRP78/BiP, was observed in CHO-K1 cells. Northern blot analysis indicated that the mutant HC I1 mRNA was transcribed at a similar level as that of wild-type. Immunohistochemical staining of the transfected cells revealed that COS-1 cells expressing the mutant HC II molecules were stained mainly in the perinuclear area. We conclude that the impaired secretion of the mutant HC II molecules, due to intracellular degradation, is the molecular pathogenesis of type I congenital HC II deficiency caused by a Pro443 to Leu mutation at reactive P2 site.
Takamasa Ohnishi, Eiji Takeda, Shiro Yogita, Hidenori Miyake, Takafumi Kinoshita, Yoshiyasu Terashima, Toshio Matsumoto and Seiki Tashiro : Effects of alendronate on bone metastases and hypercarcemia after surgery for hepatocellular carcinoma, Japanese Journal of Clinical Oncology, Vol.30, No.9, 410-413, 2000.
(Summary)
Alendronate, a bisphosphonate compound, lowers serum calcium in patients with cancer-associated hypercalcemia through its inhibitory effect on bone resorption and as a result symptoms associated with hypercalcemia improve. This study was carried out to investigate the effects of alendronate in patients with hypercalcemia due to bone metastasis of hepatocellular carcinoma (HCC). Two patients were evaluated. Their corrected serum calcium and alpha-fetoprotein (AFP) levels and their computed tomography (CT), bone scintigraphy and magnetic resonance imaging (MRI) findings were evaluated before and during alendronate treatment. After treatment, not only the corrected serum calcium levels but also AFP levels and bone pain decreased; in addition, the regression of the metastatic focus was noted in the MRI analysis. These tumor inhibitory effects of alendronate have not been reported in HCC before; and alendronate might serve to prevent bone metastases in patients with HCC. In conclusion, two patients who developed hypercalcemia associated with bone metastasis after surgery for HCC were treated with alendronate and they experienced alleviation of the pain due to bone metastasis, improvement of their quality of life and a marked decrease in AFP levels with tumor regression.
(Keyword)
Aged / Alendronate / Bone Neoplasms / Carcinoma, Hepatocellular / Female / Humans / Hypercalcemia / Liver Neoplasms / Male
Takao Mitsui, Masakazu Kawajiri, Makoto Kunishige, Takenori Endo, Masashi Akaike, Kenji Aki and Toshio Matsumoto : Functional association between nicotinic acetylcholine receptor and sarcomeric proteins via actin and desmin filaments, Journal of Cellular Biochemistry, Vol.77, No.4, 584-595, 2000.
Ayako Kagawa, Hiroyuki Azuma, Masashi Akaike, Yasuhiko Kanagawa and Toshio Matsumoto : Aspirin Reduces Apolipoprotein(a) (Apo(a)) Production in Human Hepatocytes by Suppression of Apo(a) Gene Transcription, The Journal of Biological Chemistry, Vol.274, No.48, 34111-34115, 1999.
(Summary)
High serum lipoprotein(a) (Lp(a)) is a risk factor for vascular disorders. Our preliminary observations suggest that, in some patients with coronary heart disease with high serum Lp(a) levels, administration of aspirin reduced Lp(a) levels. Therefore, we aimed to analyze the effects of aspirin on the production of apo(a), the expression of apolipoprotein(a) (apo(a)) mRNA and the transcriptional activity of apo(a) gene promoter. Aspirin (5 mM) reduced the apo(a) levels in culture medium of human hepatocytes and suppressed apo(a) mRNA expression to 73% and 85% of the controls, respectively. Aspirin also reduced the transcriptional activity of apo(a) gene transfected into HepG2 hepatoma cells in a dose-dependent manner, with a maximal effect at 5 mM (44.3 +/- 1.5% of the control). Sodium salicylate (5 mM) also reduced apo(a) gene transcription, whereas indomethacin (10 microM) had no effect. Deletion analysis of apo(a) gene promoter showed that promoter region extending from -30 to +138 is critical for the effect of aspirin. Furthermore, enhanced production, mRNA expression, and gene transcription of apo(a) by interleukin-6 were also inhibited by aspirin. These results demonstrate that aspirin reduces apo(a) production from hepatocytes via reduction of the transcriptional activity of apo(a) gene with suppression of apo(a) mRNA expression. The suppression of apo(a) production by aspirin may at least in part play a role in the anti-atherogenic effect of aspirin in vascular disorders.
Ryuzo Tani, Shuji Ozaki, Masaaki Kosaka, Soichiro Fujiwara, Hironobu Shibata, Shingo Wakatsuki and Toshio Matsumoto : Fas ligand-induced apoptosis of hepatocytes in natural killer cell leukaemia, British Journal of Haematology, Vol.106, No.3, 709-712, 1999.
(Summary)
Neoplastic natural killer (NK) cells overexpress Fas ligand (FasL), which may cause damage of Fas-bearing tissues. We report a patient with NK cell leukaemia who developed liver injury after pharyngitis. The NK leukaemic cells expressed functional FasL. In addition to soluble FasL, serum levels of interleukin-6 and interferon-gamma were increased dramatically when liver injury was aggravated. Moreover, hepatocytes expressed Fas and apoptotic hepatocytes were detected in the portal areas. These findings are consistent with the notion that inflammatory cytokines enhance the sensitivity to FasL and trigger apoptosis of hepatocytes in NK cell malignancies.
Shuji Ozaki, Masaaki Kosaka, Yuji Wakahara, Yasuko Ozaki, Masayuki Tsuchiya, Yasuo Koishihara, Tetsuya Goto and Toshio Matsumoto : Humanized anti-HM1.24 antibody mediates myeloma cell cytotoxicity that is enhanced by cytokine stimulation of effector cells, Blood, Vol.93, No.11, 3922-3930, 1999.
(Summary)
To develop a new immunotherapy for multiple myeloma, we have generated a monoclonal antibody (MoAb) that detects a human plasma cell-specific antigen, HM1.24. Our previous study has shown that mouse anti-HM1.24 MoAb inhibits the proliferation of human myeloma cells implanted into severe combined immunodeficiency mice. In this report, we evaluated the antitumor activity of the humanized anti-HM1.24 MoAb (IgG1kappa), which was constructed by grafting the complementarity-determining regions. In contrast to the parent mouse MoAb, humanized anti-HM1.24 MoAb mediated antibody-dependent cellular cytotoxicity (ADCC) against both myeloma cell lines and myeloma cells from patients in the presence of human peripheral blood mononuclear cells (PBMCs). The PBMCs from untreated myeloma patients exhibited ADCC activity as efficiently as those of healthy donors. Although decreased ADCC activity of PBMCs was observed in patients who responded poorly to conventional chemotherapy, it could be significantly augmented by the stimulation with interleukin-2 (IL-2), IL-12, or IL-15. There was a strong correlation between the percentage of CD16(+) cells and ADCC activity in the PBMCs of myeloma patients. Moreover, peripheral blood stem cell collections from myeloma patients contained higher numbers of CD16(+) cells than PBMCs and exhibited ADCC activity that was enhanced by IL-2. These results indicate that humanized anti-HM1.24 MoAb has potential as a new therapeutic strategy in multiple myeloma and that treatment of effector cells with immunomodulating cytokines can restore the effect of humanized anti-HM1.24 MoAb in patients with diminished ADCC activity.
A 33-year-old man with a 4-year history of Crohn's disease presented with marked ascites and an abdominal tumor. Two M-protein peaks, immunoglobulin (Ig) G-kappa and IgA-kappa, were detected in the serum. Neoplastic lymphoplasmacytic cells were infiltrated in the bone marrow and ascites. Histological examination of the abdominal tumor showed marked proliferation of lymphoplasmacytic cells that were positive for either IgG or IgA. Moreover, DNA sequences of the expressed IgG and IgA genes were different in the complementarity-determining region 3. These results suggest that chronic inflammation in Crohn's disease contributes to the simultaneous development of biclonal lymphoplasmacytic immunocytoma of the small intestine.
M. Kawajiri, Takao Mitsui, Masayuki Shono and Toshio Matsumoto : Quantitative analysis of immunofluorescent signals for dystrophin, beta-dystroglycan and myosin skeletal muscle by epifluorescence microscopy., Biotech-Histochem, Vol.74, No.2, 92-97, 1999.
Shuji Ozaki, Masaaki Kosaka, Masafumi Harada, Hiromu Nishitani, Masaaki Odomi and Toshio Matsumoto : Radioimmunodetection of human myeloma xenografts with a monoclonal antibody directed against a plasma cell specific antigen, HM1.24, Cancer, Vol.82, No.11, 2184-2190, 1998.
(Keyword)
monoclonal antibody / multiple myeloma / F(ab')2 fragment / plasma cell / severe combined immunodeficiency mouse
Shuji Ozaki, Koji Ogasahara, Masaaki Kosaka, Toshi Inoshita, Shingo Wakatsuki, Hisanori Uehara and Toshio Matsumoto : Hepatosplenic gamma delta T-cell lymphoma associated with hepatitis B virus infection, The Journal of Medical Investigation : JMI, Vol.44, No.3-4, 215-217, 1998.
(Summary)
Hepatitis B virus (HBV) infection has been implicated in the development of hepatocellular and hematopoietic malignancies. We describe a patient with chronic hepatitis B who developed hepatosplenic gamma delta T-cell lymphoma. A 45-year-old woman presented with marked hepatosplenomegaly and hepatic failure during the course of chronic hepatitis B. Peripheral blood examination revealed 57% abnormal lymphoid cells which expressed the gamma delta T-cell receptor. The cytogenetic analysis of tumor cells showed an abnormal karyotype; 47, XX, -13, +2mar in all 20 metaphases examined. A clonal rearrangement of the T-cell receptor genes was demonstrated by Southern blot analysis, showing monoclonal expansion of tumor cells. A liver biopsy specimen showed fibrosis of the portal areas and sinusoidal infiltration of tumor cells. HBV infection was documented by the presence of IgG anti-HBc and anti-HBs antibodies in serum. Although HBV-DNA was not detected in tumor cells by polymerase chain reaction analysis, there is a possibility that proliferation of gamma delta T cells in response to HBV infection played a role in the pathogenesis of hepatosplenic gamma delta T-cell lymphoma.
We encountered two patients with acute pandysautonomia who subacutely exhibited extensive autonomic dysfunction after antecedent infections. Although these patients had been suffering from autonomic disturbance for several months, they both had a good clinical course after plasma exchange and intravenous immunoglobulin therapy. Thin-layer chromatography (TLC)-immunostaining did not demonstrate any antibodies against gangliosides, but immunoblot analysis showed antibodies against a neuroblastoma cell line, SH-SY5Y, in serum samples. Furthermore, ganglionic acetylcholine receptor autoantibodies were detected in one patient. These findings suggest that neuronal antibodies against the autonomic nervous system play an important role in the pathogenesis of acute pandysautonomia.
(Keyword)
Aged / Autoantibodies / Autoimmune Diseases of the Nervous System / Autonomic Nervous System Diseases / Humans / Immunoblotting / Immunoglobulins, Intravenous / Male / Neurons / Plasma Exchange / Receptors, Cholinergic
七條 加奈, 関本 悦子, 三原 愛, 大田 加与, 田中 洋一, 大島 隆志, 柴田 泰伸, Toshihiro Hashimoto, Shuji Ozaki, Masahiro Abe, Toshio Matsumoto and 若槻 真吾 : Successful treatment of relapsed/refractory Hodgkin's lymphoma with tandem transplantation, The Journal of the Japanese Society of Internal Medicine, Vol.93, No.10, 2210-2212, 2004.
Masahiro Abe, Toshio Matsumoto and 小阪 昌明 : Effect of bisphosphonate on myeloma bone disease, The Japanese Journal of Clinical Hematology, Vol.43, No.5, 349-352, 2002.
(Keyword)
Bisphosphonate / Osteolysis / osteoclast / Bone metabolism
(Link to Search Site for Scientific Articles)
● CiNii @ National Institute of Informatics (NAID): 10010364770
Takeshi Kondo, Itsuro Endo and Toshio Matsumoto : [The pathology, diagnosis and therapy on osteoporosis]., Nihon Rinsho. Japanese Journal of Clinical Medicine, Vol.72, No.10, 1774, Oct. 2014.
(Summary)
The increase of elderly population in Japan suggests the importance of the prevention of osteoporotic fracture. Falls and fractures account for around 10% of the causes for requiring care services in Japan. The Japanese criteria for initiating pharmacological treatment to prevent fragility fracture were revised in 2011. There are many kinds of anti-osteoporosis drugs including bisphosphonates, SERM, teriparatide, and denosumab that have been proven to reduce fractures. Thus, it is important to select drugs appropriate for each osteoporotic patients considering the mechanisms of drug action, their efficacy and side effects. In this article, we review pathophysiology, diagnosis and treatment of osteoporosis.
Itsuro Endo and Toshio Matsumoto : [Bone Structural Properties and Bone Strength. Bone architecture and strength on unloading]., Clinical Calcium, Vol.23, No.7, 1013-1019, Jul. 2013.
(Summary)
The bone loss due to space flight or prolonged bed rest observes early stage of unloading and causes both decreased bone formation and increased bone resorption. Mechanical unloading induced not only both tarbecular and cortical bone loss but also greater decline bone structure in weight-bearing bone. These findings and further examination concern about pathophysiolosy will allow for better understanding of unloading-associated bone loss and for development of effective countermeasures.
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 23811590
Itsuro Endo and Toshio Matsumoto : [Space flight/bedrest immobilization and bone. Bisphosphonate and the loss of bone mineral due to space flight or prolonged bed rest]., Clinical Calcium, Vol.22, No.12, 1863-1870, Dec. 2012.
(Summary)
Bone mass and strength are maintained by appropriate weight bearing. The loss of bone mineral due to space flight or prolonged bed rest has been recognized by space scientists and physicians. In spite of the wealth of knowledge obtained thus far, many questions remain unanswered regarding the mechanism of bone loss as well as the factors affecting these skeletal processes. Bisphosphonates have a potential to become countermeasures against space flight-induced or disuse osteoporosis. In this review, the effect and the possible role of biphosphonates on the prevention and treatment of unloading-induced osteoporosis are summarized and future prospects are discussed.
(Keyword)
Bed Rest / Bone and Bones / Calcification, Physiologic / Diphosphonates / Humans / Space Flight / Time Factors
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 23187079
Itsuro Endo and Toshio Matsumoto : Effect of vitamin D on bone and immune system, Journal of Clinical and Experimental Medicine, Vol.242, No.9, 751-757, Sep. 2012.
(Keyword)
ビタミンD充足域 / 転倒抑止効果 / 骨免疫学 / 免疫調節作用
(Link to Search Site for Scientific Articles)
● CiNii @ National Institute of Informatics (NAID): 40019389769
Shusuke Yagi, Ken-ichi Aihara, Yasumasa Ikeda, Masashi Akaike, Masataka Sata and Toshio Matsumoto : Effects of Statins on Cardiorenal Syndrome., International Journal of Vascular Medicine, Vol.2012, 162545, Jun. 2012.
(Summary)
Cardiovascular disease and renal disease have a close relationship that forms a vicious cycle as a cardiorenal syndrome (CRS). Oxidative stress, endothelial dysfunction, and vascular inflammation could be therapeutic targets when the renin-angiotensin-aldosterone system is activated by accumulation of conventional cardiovascular risk factors; however, a strategy for management of CRS has not been established yet. Statins, HMG-CoA reductase inhibitors, have not only cholesterol-lowering effects but also pleiotropic effects on cardiovascular systems, including anti-inflammatory and antioxidant effects and improvement of nitric oxide bioavailability. Since recent studies have indicated that statins have beneficial effects on chronic kidney disease and heart failure as well as coronary artery disease in cholesterol-lowering-dependent/independent manners, treatment with statins might be a successful strategy for preventing deterioration of CRS.
Itsuro Endo and Toshio Matsumoto : [New approved drugs for osteoporosis in Japan]., Clinical Calcium, Vol.22, No.6, 870-876, Jun. 2012.
(Summary)
These 2 years, we had had new therapeutic options for osteoporotic patients, for example minodoronate, bazedoxifene, teriparatide and eldecalcitol in Japan. Minodoronate and eldecalcitol came from Japan and they had many clinical evidences on Japanese patients. Teriparatide is a powerful anabolic agent for bone, had been provided as daily or weekly subcutaneous injection. These reagents may become helpful drug for osteoporotic patients. This review shows the character and clinical evidences of these drugs.
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 22653027
Yasumasa Ikeda, Ken-ichi Aihara, Sumiko Yoshida, Masashi Akaike and Toshio Matsumoto : Effects of androgens on cardiovascular remodeling., The Journal of Endocrinology, Apr. 2012.
(Summary)
Androgens, the male sex hormones, exert various biological effects on many target organs through the transcriptional effects of the nuclear androgen receptor (AR). ARs are expressed not only in classical target organs, such as the brain, genital organs, bone, and skeletal muscles, but also in the cardiovascular system. Because the female sex hormones estrogens are well known to protect against cardiovascular disease, sex has been considered to have a significant clinical impact on cardiovascular mortality. However, the influence of androgens on the cardiovascular system has not been fully elucidated. To clarify this issue, we analyzed the effects of administration of angiotensin II and doxorubicin, an anticancer agent, in a loading model in male wild-type and AR-deficient mice. In this review, we focus on the actions of androgens as potential targets for the prevention of cardiovascular diseases in males.
Itsuro Endo and Toshio Matsumoto : [Frontiers in vitamin D; basic research and clinical application. Eldecalcitol: the effect on bones and calcium metabolism]., Clinical Calcium, Vol.21, No.11, 103-110, Nov. 2011.
(Summary)
Eldecalcitol is a new active vitamin D compound, bearing a hydroxypropyloxy residue at the 2-position of 1, 25 (OH) D . In ovariectomized rats, eldecalcitol increased vertebral bone mass and bone strength by inhibiting bone resorption and maintaining bone formation. In randomized, placebo-controlled, double-blinded clinical trial for osteoporotic subjects, eldecalcitol increased lumber vertebral and hip bone mineral density independent of vitamin D status. Furthermore, in patients with osteoporosis, eldecalcitol treatment was associated with a lower risk of vertebral and wrist fractures, with greater decrease in bone turnover markers compared with alfacalcidol. The incidence of adverse events was similar between the two treatments. Therefore, eldecalcitol can become a new treatment of choice for osteoporosis.
(Keyword)
Animals / Bone Density / Bone Density Conservation Agents / Bone Remodeling / Bone Resorption / Bone and Bones / Calcium / Disease Models, Animal / Dose-Response Relationship, Drug / Female / Fractures, Bone / Fractures, Spontaneous / Humans / Osteogenesis / Osteoporosis, Postmenopausal / Ovariectomy / Rats / Vitamin D
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 22040826
Itsuro Endo and Toshio Matsumoto : Progress and perspectives in bone research, Nihon Rinsho. Japanese Journal of Clinical Medicine, Vol.69, No.7, 1175-1180, Jul. 2011.
(Keyword)
osteoporosis / bone metabolism
(Link to Search Site for Scientific Articles)
● CiNii @ National Institute of Informatics (NAID): 40018884214
Itsuro Endo and Toshio Matsumoto : Parathyroid neoplasms: a state and view of clinical research, Nihon Rinsho. Japanese Journal of Clinical Medicine, Vol.69, 455-460, Mar. 2011.
(Keyword)
parathyroid / neoplasm
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 21834160
● CiNii @ National Institute of Informatics (NAID): 40018749414
ED-71 is a new vitamin D receptor ligand, bearing a hydroxypropoxy substituent at the 2β-position of 1α, 25 (OH) (2)D(3). In ovariectomized rats, ED-71 increased vertebral bone mass and bone strength by inhibiting bone resorption and maintaining bone formation. In randomized, placebo-controlled, double-blinded clinical trial for osteoporotic subjects, ED-71 increased lumber vertebral and hip bone mineral density independently vitamin D status. Furthermore, ED-71 may have a better osteoprotective effect than alfacalcidol and suggest that ED-71 may serve as a new generation of active vitamin D with anti-fracture efficacy in osteiporotic subjects.
(Keyword)
Animals / Bone Density / Bone Resorption / Dose-Response Relationship, Drug / Female / Fractures, Bone / Humans / Lumbar Vertebrae / Osteogenesis / Osteoporosis / Randomized Controlled Trials as Topic / Rats / Stimulation, Chemical / Vitamin D
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 21187594
Ken-ichi Aihara, Yasumasa Ikeda, Shusuke Yagi, Masashi Akaike and Toshio Matsumoto : Transforming Growth Factor-1 as a Common Target Molecule for Development of Cardiovascular Diseases, Renal Insufficiency and Metabolic Syndrome., Cardiology Research and Practice, Vol.2011, 175381, Dec. 2010.
(Summary)
Transforming growth factor-1 (TGF-1) is a polypeptide member of the transforming growth factor superfamily of cytokines. It is a secreted protein that performs many cellular functions including control of cell growth, cell proliferation, cell differentiation and apoptosis. In the cardiovascular system, TGF-1 plays pivotal roles in the pathogenesis of hypertension, restenosis after percutaneous coronary intervention, atherosclerosis, cardiac hypertrophy and heart failure. In addition, TGF-1 has been shown to be increased in adipose tissue of obese subjects with insulin resistance. Furthermore, TGF-1 is a potent initiator of proliferation of renal mesangial cells leading to chronic kidney disease. Some currently available agents can manipulate TGF-1 expression leading to amelioration of cardiovascular diseases. Thus, an understanding of interactions between chronic kidney disease and metabolic syndrome and the development of cardiovascular diseases is an important issue, and attention should be given to TGF-1 as a crucial factor for regulation and modulation of those pathological conditions.
Itsuro Endo and Toshio Matsumoto : [Secondary osteoporosis UPDATE. Drugs under development for metabolic bone disease]., Clinical Calcium, Vol.20, No.5, 700-708, May 2010.
(Summary)
For the treatment of osteoporosis, anti-resorptive agents including bisphosphonates and raloxifene are widely used. As new anti-resorptive drugs, anti-RANKL antibody and cathepsin K inhibitor are under development. Among bone anabolic agents, daily subcutaneous injection of teriparatide will soon become available in Japan. In addition, new anabolic agents such as calcilitycs and anti-sclerostin antibody are under clinical or preclinical development for the treatment of osteoporosis.
(Keyword)
Anabolic Agents / Bone Density Conservation Agents / Bone Diseases, Metabolic / Cathepsins / Diphosphonates / Drug Discovery / Humans / Osteoporosis / RANK Ligand / Raloxifene / Selective Estrogen Receptor Modulators / Teriparatide
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 20445281
Ken-ichi Aihara, Hiroyuki Azuma, Masashi Akaike, Masataka Sata and Toshio Matsumoto : Heparin Cofactor II as a Novel Vascular Protective Factor Against Atherosclerosis., Journal of Atherosclerosis and Thrombosis, Vol.16, No.5, 523-531, Sep. 2009.
(Summary)
Heparin cofactor II (HCII) specifically inhibits thrombin action at the site of vascular wall injury. We encountered a congenital HCII deficiency patient with advanced multiple atherosclerotic lesions. This patient led us to conduct clinical studies to examine the role of HCII against atherosclerosis. We found that the incidence of in-stent restenosis after percutaneous coronary intervention, severity of carotid atherosclerosis and prevalence of peripheral arterial disease are inversely associated with plasma HCII activity. In order to clarify the vascular protective action of HCII, we generated HCII- deficient mice by gene targeting. In contrast to a previous study, HCII(-/-) mice were embryonically lethal. In HCII(+/-) mice, accelerated intimal hyperplasia and frequent thrombosis were observed after cuff or wire injury of femoral arteries. The number of protease-activated receptor-1 (PAR-1) -positive cells and the gene expression levels of inflammatory cytokines and chemokines were increased in the thickened vascular walls of HCII(+/-) mice. The accelerated intimal hyperplasia in HCII+/- mice with vascular injury was attenuated by human HCII administration. Furthermore, HCII deficiency exaggerated aortic plaque formation with increased oxidative stress in apolipoprotein E(-/-) mice. These results demonstrate that HCII protects against thrombin-induced vascular remodeling in both humans and mice and suggest that HCII is a predictive biomarker and therapeutic target for atherosclerosis.
Ken-ichi Aihara, Hiroyuki Azuma and Toshio Matsumoto : Vitamin D-vitamin D receptor system regulates antithrombogenicity in vivo., Clinical Calcium, Vol.16, No.7, 1173-1179, Jul. 2006.
(Summary)
Although it has been well documented that vitamin D receptor (VDR) activation influences the expression of various genes involved in calcium homeostasis and cell differentiation, the physiological role of VDR action in hemostasis remains unclear. We studied thrombogenicity in normocalcemic VDR knock-out (KO) mice on a high calcium diet in comparison with that in wild-type mice and that in hypocalcemic VDRKO mice fed a regular diet. Platelet aggregation was significantly enhanced in normocalcemic VDRKO mice. Aortic endothelial nitric-oxide (NO) synthase expression and urinary NOx excretion were reduced in hypocalcemic VDRKO mice but not in normocalcemic VDRKO mice. The gene expression of antithrombin in the liver and that of thrombomodulin in the aorta, liver and kidney were down-regulated in hypo- and normocalcemic VDRKO mice, whereas tissue factor gene expression in the liver and kidney was up-regulated in VDRKO mice regardless of plasma calcium level. Furthermore, VDRKO mice manifested an exacerbated multi-organ thrombus formation after exogenous lipopolysaccharide injection regardless of the calcemic conditions. These results demonstrate that the vitamin D-VDR system plays a pivotal role in antithrombogenicity in vivo.
Jumpei Teramachi, Hirofumi Tenshin, Masahiro Hiasa, Oda Asuka, Takeshi Harada, Shingen Nakamura, Hirokazu Miki, Tatsuji Haneji, Itsuro Endo, Toshio Matsumoto and Masahiro Abe : Therapeutic impact of TAK1 inhibition on myeloma tumor progression and bone destruction, 8th International Workshop on Advances in the Molecular Pharmacology and Therapeutics of Bone and other Musculoskeletal Diseases and Cancer and Bone Society 2018 Meeting, Oxford, Jun. 2018.
Itsuro Endo, Dong Bingzi, Ohnishi Yukiyo, Kondo Takeshi, Masahiro Hiasa, Jumpei Teramachi, Toshio Matsumoto, Masahiro Abe, Seiji Fukumoto and Tatsuji Haneji : Decreased bone strength induced by persistent activation of calcium-sensing receptor, American Society for Bone and Mineral Research (ASBMR) 2017 Annual Meeting, Denver, Sep. 2017.
Jumpei Teramachi, Masahiro Hiasa, Oda Asuka, Hirofumi Tenshin, Ryota Amachi, Takeshi Harada, Shingen Nakamura, Hirokazu Miki, Itsuro Endo, Tatsuji Haneji, Toshio Matsumoto and Masahiro Abe : TAK1 inhibition impairs myeloma cell-bone marrow interaction to reduce myeloma tumor growth and bone destruction, American Society for Bone and Mineral Research (ASBMR) 2017 Annual Meeting, Denver, Sep. 2017.
Jumpei Teramachi, Masahiro Hiasa, Oda Asuka, Hirofumi Tenshin, Ryota Amachi, Takeshi Harada, Shingen Nakamura, Hirokazu Miki, Itsuro Endo, Tatsuji Haneji, Toshio Matsumoto and Masahiro Abe : Therapeutic impact of TAK1 inhibition on myeloma tumor progression and bone destruction, International Society for Experimental Hematology 46th Annual Scientific Meeting, Frankfurt, Aug. 2017.
Hirofumi Tenshin, Jumpei Teramachi, A Oda, Ryota Amachi, Masahiro Hiasa, A Baterdene, Keiichiro Watanabe, Shingen Nakamura, Hirokazu Miki, Itsuro Endo, Itsuro Endo, Eiji Tanaka, Toshio Matsumoto and Masahiro Abe : Osteoclasts utilize TRAIL for their NF-B activation, but TAK1 inhibition resumes TRAIL-induced apoptosis in osteoclasts., Australian and New Zealand Bone and Mineral Society 2017, Brisbane, Australia., Jun. 2017.
Jumpei Teramachi, Masahiro Hiasa, Oda Asuka, Hirofumi Tenshin, Ryota Amachi, Takeshi Harada, Shingen Nakamura, Hirokazu Miki, Itsuro Endo, Akihito Yamamoto, Tatsuji Haneji, Toshio Matsumoto and Masahiro Abe : Therapeutic impact of TAK1 inhibition on myeloma tumor progression and bone destruction, Cancer and Bone Society Conference 2017, Indianapolis, May 2017.
Hirofumi Tenshin, Jumpei Teramachi, Ryota Amachi, Masahiro Hiasa, Keiichiro Watanabe, Toshio Matsumoto, Masahiro Abe and Eiji Tanaka : TRAIL Stimulates Osteoclast Differentiation and Survival via TAK1 Activation., 95th General Session & Exhibition of the IADR program book, San Francisco, Mar. 2017.
Kiyoe Kurahashi, Itsuro Endo, Nakamura Maiko, Ohnishi Yukiyo, Takeshi Kondo, Aizawa Shinichi, Toshio Matsumoto, Seiji Fukumoto and Masahiro Abe : Glucose intolerance induced by persistent activation of calcium-sensing receptor, American Society for Bone and Mineral Research 2016 Annual Meeting, Atlanta, Sep. 2016.
Jumpei Teramachi, Masahiro Hiasa, Asuka Oda, Hirofumi Tenshin, Ryota Amachi, Takeshi Harada, Shingen Nakamura, Kiyoe Kurahashi, Takeshi Kondo, Hirokazu Miki, Itsuro Endo, Toshio Matsumoto and Masahiro Abe : TAK-1 inhibition disrupts Pim-2-associated and Pim-2-independent key signaling pathways to effectively suppress tumor growth and restore bone formation in myeloma, American Society for Bone and Mineral Research 2016 Annual Meeting, Atlanta, Sep. 2016.
Hirofumi Tenshin, Jumpei Teramachi, A Oda, Ryota Amachi, Bingzi Dong, Masahiro Hiasa, Keiichiro Watanabe, Ryota Amachi, S Nakamura, H Miki, Itsuro Endo, Eiji Tanaka, Toshio Matsumoto and Masahiro Abe : Osteoclasts utilize an apoptosis-inducer TRAIL as a stimulator for osteoclastogenesis Critical roles of the TAK-1-Pim-2 signaling induced by RANK ligand and TRAIL., ANZBMS 2016 Annual Meeting, Gold Coast, Aug. 2016.
Hirofumi Tenshin, Jumpei Teramachi, A Oda, Ryota Amachi, Masahiro Hiasa, Keiichiro Watanabe, S Nakamura, H Miki, I Endo, Eiji Tanaka, Toshio Matsumoto and Masahiro Abe : TRAIL is not a proapoptotic but rather anti-apoptotic mediator for osteoclasts to stimulate their differentiation and survival, ASBMR 2015 Annual Meeting, Seattle, Oct. 2015.
Jumpei Teramachi, Masahiro Hiasa, Asuka Oda, Hirofumi Tenshin, Ryota Amachi, Takeshi Harada, Keiichiro Watanabe, Shiroh Fujii, Kumiko Kagawa, Shingen Nakamura, Hirokazu Miki, Itsuro Endo, Tatsuji Haneji, Toshio Matsumoto and Masahiro Abe : Pivotal role of TAK-1 in tumor growth and bone destruction in myeloma: Therapeutic impact of TAK-1 inhibition, American Society for Bone and Mineral Research 2015 Annual Meeting, Oct. 2015.
Akiko Hata, Yosuke Shikama, Nanako Aki, Chisato Kosugi, Hiroya Kobayashi, Masashi Miyoshi, Takayuki Nakao, Ayako Tamura, Takako Ichihara, Takako Minagawa, Yumi Kuwamura, Toshio Matsumoto and Makoto Funaki : Serum Adipocyte Fatty Acid-binding Protein Is Related to the Development of Metabolic Syndrome in Japanese Male Workers, Diabetes, Vol.63, No.Suppl.1, A.388, Jun. 2014.
Ryota Amachi, Masahiro Abe, Masahiro Hiasa, Keiichiro Watanabe, S Fujii, T Harada, H Miki, S Nakamura, I Endo, Eiji Tanaka and Toshio Matsumoto : Acidic conditions epigenetically repress the TRAIL receptor DR4 in myeloma cells to confer their resistance to TRAIL, ASBMR 2013 Annual Meeting,, Baltimore, Oct. 2013.
Keiichiro Watanabe, Masahiro Abe, H Mori, Ryota Amachi, Masahiro Hiasa, T Harada, S Fujii, S Nakamura, H Miki, K Kagawa, I Endo, Eiji Tanaka and Toshio Matsumoto : Potent induction of bone formation in myeloma bone lesions by the cathepsin K inhibitor KK1-300-01 in combination with the proteasome inhibitor bortezomib, ASBMR 2013 Annual Meeting,, Baltimore, Oct. 2013.
Akio Kuroda, Takeshi Kondo, Ken-ichi Aihara, Itsuro Endo, T Yasuda, H Kaneto, T Matsuoka, Toshio Matsumoto and Munehide Matsuhisa : The characteristics of type 1 diabetes patients who use insulin pump with square-wave bolus insulin., 73th America Diabetes Association (poster), Jun. 2013.
Harada Takeshi, Ozaki Shuji, Oda Asuka, Iwasa Masami, Shiroh Fujii, Shingen Nakamura, Hirokazu Miki, Kumiko Kagawa, Masahiro Abe, Shibata Hironobu, Akishige Ikegame, Daisuke Tsuji, Ito Kohji, Ri Masaki, Iida Shinsuke, Shiotsu Yukimasa, Kawai Shigeto, Yamada-Okabe Hisafumi and Toshio Matsumoto : Combination therapy of a defucosylated anti-HM1.24 monoclonal antibody plus Ienalidomide induces marked antibody-dependent cellular cytotoxicity and inhibits the clonogenic potential of myeloma cancer stem-like cells. Atlanta, Dec. 2012., The 54th Annual Meeting of the American Society of Hamatology, Dec. 2012.
T Harada, Shuji Ozaki, A Oda, M Iwasa, Shiroh Fujii, Shingen Nakamura, Hirokazu Miki, Kumiko Kagawa, Masahiro Abe, Hirofumi Shibata, Akishige Ikegame, Daisuke Tsuji, Kouji Itou, M Ri, S Iida, Y Shiotsu, S Kawai, H Yamada-Okabe and Toshio Matsumoto : Combination Therapy of a Defucosylated Anti-HM1.24 Monoclonal Antibody Plus Lenalidomide Induces Marked Antibody-Dependent Cellular Cytotoxicity and Inhibits the Clonogenic Potential of Myeloma Cancer Stem-Like Cells., 54th ASH Annual Meeting and Exposition, USA, Atlanta, Dec. 2012.
Ryota Amachi, Masahiro Abe, Ryota Amachi, Keiichiro Watanabe, S Fujii, T Harada, H Miki, S Nakamura, A Oda, Masahiro Hiasa, Eiji Tanaka and Toshio Matsumoto : An acidic milieu suppresses DR4 editing to cause myeloma resistance to TRAIL, ASEAN plus and Tokushima Joint International Conference, Yogjakarta, Indonesia, Dec. 2012.
Masahiro Abe, Masahiro Hiasa, Watanabe ken-ichiro, Nakamura Shingen, Harada Takeshi, Itsuro Endo and Toshio Matsumoto : Prevention of tumor growth and bone destruction in myeloma by Pim kinase inhibition, 12th CIBD International Meeting on Cancer Induced Bone Disease (CIBD) Lyon, Nov. 2012, Nov. 2012.
Masahiro Hiasa, Keiichiro Watanabe, Shingen Nakamura, Harada Takeshi, Itsuro Endo, Toshio Matsumoto and Masahiro Abe : Prevention of tumor growth and bone destruction in myeloma by Pim kinase inhibition, 12th Int'l Meeting on Cancer Induced Bone Disease, Lyon, Nov. 2012.
Ken-ichi Aihara, Sumiko Yoshida, Mizuho Kinouchi, Takeshi Kondo, Akio Kuroda, Itsuro Endo, Munehide Matsuhisa and Toshio Matsumoto : Diabetes Spoils the Favorable Effect of HDL-Cholesterol on Endothelial Function in the Elderly with Cardiovascular Risk Factors, American Heart Association Scientific Sessions 2012, ロサンゼルス, Nov. 2012.
Sumiko Yoshida, Ken-ichi Aihara, Takayuki Ise, Yuka Ueda, Yasumasa Ikeda, Takashi Iwase, Masashi Akaike, Masataka Sata and Toshio Matsumoto : Androgen Receptor is Required for Cellular Survival and Angiogenesis in Response to Ischemia via Activation of VEGF Receptor Signaling Pathway Regardless of Sex, American Heart Association Scientific Session 2012, Nov. 2012.
Yasumasa Ikeda, Ken-ichi Aihara, Sumiko Yoshida, Masataka Sata, Masashi Akaike, Toshio Matsumoto and Toshiaki Tamaki : Heparin Cofactor II Promotes Angiogenesis in Response to Ischemic Hindlimb via an AMPK-eNOS-dependent Manner, American Heart Association Scientific Sessions 2012, Nov. 2012.
Sumiko Yoshida, Ken-ichi Aihara, Takayuki Ise, Yuka Ueda, Yasumasa Ikeda, Takashi Iwase, Masashi Akaike, Masataka Sata and Toshio Matsumoto : Eicosapentaenoic acid administration ameliorates cardiac remodeling in humans and protects against Ang II-induced cardiovascular remodeling via attenuation of oxidative stress in mice., American Heart Association Scientific Sessions 2012, ロサンゼルス, Nov. 2012.
Keiichiro Watanabe, Masahiro Abe, Ryota Amachi, Masahiro Hiasa, T Harada, S Fujii, S Nakamura, H Miki, K Kagawa, H Mori, I Endo, Eiji Tanaka and Toshio Matsumoto : Restoration of bone formation in myeloma osteolytic lesions by the cathepsin K inhibitor KK1-300-01, 34th ASBMR meeting, Minneapolis, MN, USA., Oct. 2012.
Masahiro Hiasa, Masahiro Abe and Toshio Matsumoto : RelB attenuates the activation of the classical NF-kB pathway to facilitate osteoblastogenesis, Sep. 2012.
Takeshi Kondo, Omatsu Takashi, Dong Bingzi, Ohnishi Yukiyo, Aizawa Shin-ichi, Itsuro Endo and Toshio Matsumoto : Interleukin(IL)-11 is required for mechanical stress-induced bone formation, Australian and New Zealand Bone and Mineral Society, Gold Coast, Sep. 2012.
Keiichiro Watanabe, Masahiro Abe, Hiroyo Mori, Ryota Amachi, Masahiro Hiasa, T Harada, S Fujii, S Nakamura, H Miki, K Kagawa, I Endo, Eiji Tanaka and Toshio Matsumoto : The cathepsin K inhibitor KK1-300-01 prevents bone destruction and resumes bone formation in myeloma osteolytic lesions, Australian & New Zealand Bone & Mineral Society 22th Annual Scientific Meeting with 1st Asia-Pacific Bone and Mineral Research meeting, Perth, Australia., Sep. 2012.
Akio Kuroda, YASUDA TETSUYUKI, TAKAHARA MITSUYOSHI, SAKAMOTO FUMIE, KASAMI RYUUICHI, MIYASHITA KAZUYUKI, MATSUOKA TAKA-AKI, Sumiko Yoshida, KONDO ERI, Itsuro Endo, Ken-ichi Aihara, KANETO HIDEAKI, Toshio Matsumoto, SHIMOMURA IICHIRO and Munehide Matsuhisa : Carbohydrate-to-Insulin Ratio is Calculated to be 300-400 Divided by Total Daily Insulin Dose in Type 1 Diabetic Patients Who Are on Insulin Pump Therapy, American Diabetes Association 72nd Scieentific Sessions, Philadelphia, Jun. 2012.
Ken-ichi Aihara, Sumiko Yoshida, Yasumasa Ikeda, Masashi Akaike and Toshio Matsumoto : Heparin cofactor II, a serine protease inhibitor, is a novel regulating factor for glucose metabolism and albuminuria, Keystone Symposia: Complications of Diabetes: Mechanisms of Injury and Failure of Repair, Mar. 2012.
Keiichiro Watanabe, Masahiro Abe, M Kawatani, Masahiro Hiasa, A Kawano, T Jinno, T Harada, Shiroh Fujii, Shingen Nakamura, Hirokazu Miki, Kumiko Kagawa, Kyoko Takeuchi, Shuji Ozaki, Eiji Tanaka, H Osada and Toshio Matsumoto : Aggravation of myeloma growth and drug resistance by an acidic created in myeloma-osteoclast interaction., ASBMR 2011 Annual Meeting, San Diego, Sep. 2011.
Takeshi Kondo, Takashi Omatsu, Yukiyo Ohnishi, Toshio Matsumoto and Itsuro Endo : Interleukin-11 is required for the maintenance of axial bone mass in mice., International Osteoporosis Foundation Annual Meeting 2011, Sep. 2011.
Itsuro Endo, Seiji Fukumoto and Toshio Matsumoto : FGF23-related hypophosphatemic diseases in Japan., oint Meeting of International Bone and Mineral Society and The Japanese Society of Bone Mineral Research, Jul. 2011.
Keiichiro Watanabe, Masahiro Abe, Cui Qu, Kawatani Makoto, Masahiro Hiasa, Nakano Ayako, Jinno Tadashi, Harada Takeshi, Shiroh Fujii, Shingen Nakamura, Miki Hirokazu, Kumiko Kagawa, Kyoko Takeuchi, Shuji Ozaki, Eiji Tanaka, Osada Hiroyuki and Toshio Matsumoto : An Acidic Mileu Created In Myeloma-Osteoclast Interaction Enhances Tumor Growth, but Triggers Anti-Myeloma Activity of Reveromycin A, a Novel Anti-Resorptive Agent, 52th American Society of Hematology, Orlando, Dec. 2010.
Cui Qu, Masahiro Abe, Miki Hirokazu, Shingen Nakamura, Keiichiro Watanabe, Akishige Ikegame, Masahiro Hiasa, Nakano Ayako, Harada Takeshi, Shiroh Fujii, Kumiko Kagawa, Kyoko Takeuchi, Shuji Ozaki and Toshio Matsumoto : Lenalidomide In Combination with Zoledronic Acid Restores the Activation and Anti-Myeloma Effects of γδT Cells Attenuated by the Bone Marrow Microenvironment, 52th American Society of Hematology, Orlando, Dec. 2010.
Sumiko Yoshida, Ken-ichi Aihara, Takayuki Ise, Yuka Ueda, Yasumasa Ikeda, Takashi Iwase, Masashi Akaike, Masataka Sata and Toshio Matsumoto : Androgen receptor is essential for cell survival and neovascularization after ischemia., American Heart Association Scientific Sessions 2010, Chicago, Nov. 2010.
Sumiko Yoshida, Ken-ichi Aihara, Takayuki Ise, Yuka Ueda, Yasumasa Ikeda, Takashi Iwase, Masashi Akaike, Masataka Sata and Toshio Matsumoto : Androgen receptor participants in ischemia-induced tissue damage and angiogenesis in male mice, 23rd Scientific Meeting of the International Society of Hypertension Vancouver, Vancouver, Sep. 2010.
Masahiro Abe, Masahiro Hiasa, Nakano A, Shingen Nakamura, Miki H, Qu C, Keiichiro Watanabe, Harada T, Kumiko Kagawa, Kyoko Takeuchi, Shuji Ozaki and Toshio Matsumoto : TIMP-3 up-regulation facilitates osteoclastogenesis and suppresses DC differentiation from monocytes in the bone marrow microenvironment in myeloma, 10th International Conference Cancer-induced Bone Disease, Sep. 2010.
Ken-ichi Aihara, Takayuki Ise, Yuka Ueda, Sumiko Yoshida, Yasumasa Ikeda, Uemoto Ryoko, Shusuke Yagi, Takashi Iwase, Hirata Yoichiro, Masashi Akaike, Masataka Sata and Toshio Matsumoto : Plasma heparin cofactor II activity is an independent determinant for cardiac remodeling in subjects with cardiovascular risk factors, 20th International Society for Heart Research(ISHR), Kyoto, May 2010.
Ken-ichi Aihara, Yuka Ueda, Takayuki Ise, Sumiko Yoshida, Yasumasa Ikeda, Uemoto Ryoko, Shusuke Yagi, Takashi Iwase, Hirata Yoichiro, Masashi Akaike, Masataka Sata and Toshio Matsumoto : Heparin cofactor II is a novel anticardiac remodeling factor against angiotensin II excess, 20th International Society for Heart Research(ISHR), Kyoto, May 2010.
Sumiko Yoshida, Ken-ichi Aihara, Takayuki Ise, Yuka Ueda, Yasumasa Ikeda, Takashi Iwase, Masashi Akaike, Masataka Sata and Toshio Matsumoto : Exacerbation of cell survival and impaired neovascularization after hindlimb ischemia in male androgen receptor null mice, 20th International Society for Heart Research(ISHR), Kyoto, May 2010.
Ken-ichi Aihara, Sumiko Yoshida, Kurahashi Kiyoe, Mizuho Kinouchi, Itsuro Endo, Yuichi Fujinaka and Toshio Matsumoto : Increased serum triglyceride is associated with left ventricular diastolic dysfunction., 14th International Congress of Endocrinology, Kyoto, Mar. 2010.
Ken-ichi Aihara, Yuichi Fujinaka, Mizuho Kinouchi, Sumiko Yoshida, Yuka Ueda, Kurahashi Kiyoe, Itsuro Endo, Uemoto Ryoko, Shusuke Yagi, Takashi Iwase, Hirata Yoichiro, Suzuki Reiko, Masashi Akaike, Masataka Sata and Toshio Matsumoto : Albuminuria is an independent aggravating factor for visceral fat obesity regardless of diabetes mellitus: a study using abdominal CT scan imaging, 14th International Congress of Endocrinology, Kyoto, Mar. 2010.
Masahiro Hiasa, Masahiro Abe, I Endo, A Nakano, Shuji Ozaki, Eiji Tanaka, Kenzo Asaoka and Toshio Matsumoto : Myeloma-bone marrow stromal cell interaction enhances osteoclastogenesis and suppresses dendritic cell differentiation from monocytes, 14th International Congress of Endocrinology, Kyoto, Mar. 2010.
Ken-ichi Aihara, Sumiko Yoshida, Yuka Ueda, Uemoto Ryoko, Takashi Iwase, Masashi Akaike, Masataka Sata and Toshio Matsumoto : Rosuvastatin attenuates left ventricular mass even in subjects without cardiac hypertrophy, 14th International Congress of Endocrinology, Kyoto, Japan, Mar. 2010.
Ken-ichi Aihara, Sumiko Yoshida, Kurahashi Kiyoe, Mizuho Kinouchi, Itsuro Endo, Yuichi Fujinaka and Toshio Matsumoto : Increased serum triglyceride is associated with left ventricular diastolic dysfunction, 14th International Congress of Endocrinology, Kyoto, Japan, Mar. 2010.
Akishige Ikegame, Shuji Ozaki, Daisuke Tsuji, Takeshi Harada, Shingen Nakamura, Hirokazu Miki, Ayako Nakano, Kumiko Kagawa, Kyoko Takeuchi, Ken-ichiro Yata, Masahiro Abe, Kouji Itou and Toshio Matsumoto : A recombinant HLA class I-specifi single-chain Fv diabody can target cancer stem cell-like side population cells in multiple myeloma, 51th Annual Meeting of the American Society of Hematolog, New Orleans, Louisiana, USA, Dec. 2009.
Masahiro Hiasa, Masahiro Abe, A Nakano, Kyoko Takeuchi, K Watanabe, Kumiko Kagawa, Ken-ichiro Yata, Kenzo Asaoka, Eiji Tanaka and Toshio Matsumoto : Bone marrow stromal cells inhibit dendritic cell differentiation and facilitate osteoclastogenesis in myeloma through the suppression of M-CSF receptor shedding in monocytes, 第26回 内藤コンファレンス, Nov. 2009.
S Nakamura, Masahiro Abe, Cui Qui, A Nakano, Oda A., Amou H., Ikegame A., Harada T., Masahiro Hiasa, H Miki, Kumiko Kagawa, Kyoko Takeuchi, Ken-ichiro Yata, Shuji Ozaki and Toshio Matsumoto : Facilitation of Osteoblast Differentiation by ATF-4 Accumulation through Proteasome Inhibition., ASH Annual Meeting, Nov. 2009.
A Nakano, Asano J., Masahiro Abe, Masahiro Hiasa, S Nakamura, H Miki, Kumiko Kagawa, Kyoko Takeuchi, Ken-ichiro Yata, Itsuro Endo, Shuji Ozaki and Toshio Matsumoto : Up-regulation of Pim-2 in myeloma cells by an interaction with bone marrow microenvironment enhances myeloma cell survival via stimulating Bad phosphorylation, ASBMR Annual Meeting, Denver, Sep. 2009.
Shusuke Yagi, Masashi Akaike, Takashi Iwase, Kenya Kusunose, T Niki, Y Hirata, Koji Yamaguchi, Kunihiko Koshiba, N Tomita, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, S Yoshida, Y Sumitomo, Ken-ichi Aihara, Toshio Matsumoto and Masataka Sata : Bosentan, an Endothelin Receptor Antagonist, Exerts Protective Actions against Systemic Sclerosis-related Peripheral Circulation Insufficiency., 73th Annual scientific meeting of the Japanese circulation society, Mar. 2009.
Shusuke Yagi, Masashi Akaike, Ken-ichi Aihara, S Yoshida, Y Sumitomo, Kenya Kusunose, T Niki, Y Hirata, Koji Yamaguchi, Kunihiko Koshiba, Takashi Iwase, N Tomita, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Toshio Matsumoto and Masataka Sata : Pitavastatin Exerts LDL Cholesterol Reduction-independent Protective Action for Cardiac and Renal Function in Patients with Dyslipidemia., 73th Annual scientific meeting of the Japanese circulation society, Mar. 2009.
Shusuke Yagi, Masashi Akaike, Ken-ichi Aihara, S Yoshida, Y Sumitomo, Kenya Kusunose, T Niki, Y Hirata, Koji Yamaguchi, Kunihiko Koshiba, Takashi Iwase, N Tomita, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Toshio Matsumoto and Masataka Sata : Plasma Aldosterone Concentration is Associated with Cognitive Impairement in Patients with Hypertension., 73th Annual scientific meeting of the Japanese circulation society, Mar. 2009.
Ken-ichiro Yata, Masahiro Abe, Oda A., Amou H., takeuchi K., Masahiro Hiasa, Nakano A., Miki H., Nakamura S., Tanaka O., Kumiko Kagawa, Shuji Ozaki and Toshio Matsumoto : Anti-myeloma effects of γδ T cells are hampered by bone marrow stromal cells but resumed by stromal cell-derived osteoblasts, Annual Meeting of the American Society of Hematology, San Francisco, Dec. 2008.
Ken-ichi Aihara, Sumiko Yoshida, Takayuki Ise, Sumitomo Yuka, Shusuke Yagi, Takashi Iwase, Kurahashi Kiyoe, Itsuro Endo, Yuichi Fujinaka, Masashi Akaike, Masataka Sata and Toshio Matsumoto : Increased serum triglyceride but not LDL cholesterol is associated with left ventricular diastolic dysfunction., Scientific Sessions 2008, American Heart Association, New Orleans, Nov. 2008.
Takayuki Ise, Ken-ichi Aihara, Sumiko Yoshida, Sumitomo Yuka, Shusuke Yagi, Takashi Iwase, Ishikawa Kazue, Masashi Akaike, Masataka Sata and Toshio Matsumoto : Plasma Heparin Cofactor II Activity Is Inversely Associated with Left Atrial Volume and Left Ventricular Diastolic Dysfunction., Scientific Sessions 2008, American Heart Association, New Orleans, Nov. 2008.
Masahiro Abe, Masahiro Hiasa, Kido S., Oda A., Amou H., takeuchi K., Ken-ichiro Yata, Shuji Ozaki and Toshio Matsumoto : TACE up-regulation in monocytes by GM-CSF and IL-4 disrupts myeloma cell-induced osteoclastogenesis while inducing dendritic cell differentiation, International Meeting on Cancer Induced Bone Disease, Scotland, Jun. 2008.
Masashi Akaike, Ken-ichi Aihara, Shusuke Yagi, Yasumasa Ikeda, Ishikawa Kazue, Takayuki Ise, Sumiko Yoshida, Sumitomo Yuka, Takashi Iwase and Toshio Matsumoto : Pitavastatin, an HMG-CoA Reductase Inhibitor, Prevents Glucocorticoid-induced Hypertension through Increased Nitric Oxide Production as a Pleiotropic Effect on Vascular Endothelial Cells, Hypertension 2008 18th Scientific Meeting of the European Society of Hypertension 22nd Scientific Meeting of the International Society of Hypertension, Berlin, Jun. 2008.
Takashi Iwase, Masashi Akaike, Shunji Nakano, Takayuki Ise, Sumiko Yoshida, Sumitomo Yuka, Shusuke Yagi, Ken-ichi Aihara, Natsuo Yasui and Toshio Matsumoto : Single erythropoietin administration with autologous blood donation - a novel strategy to enhance mobilization of endothelial progenitor cells, 22nd Scientific Meeting of the International Society of Hypertension 2008, Berlin, Germany, Berlin, Jun. 2008.
Sumitomo Yuka, Ken-ichi Aihara, Takayuki Ise, Sumiko Yoshida, Shusuke Yagi, Takashi Iwase, Masashi Akaike and Toshio Matsumoto : Acceleration of angiotensin II-induced cardiac remodeling through enhancement of oxidative stress in heparin cofactor II knockout mice, 22nd Scientific Meeting of the International Society of Hypertension 2008, Berlin, Germany, Berlin, Jun. 2008.
Ken-ichi Aihara, Takayuki Ise, Sumiko Yoshida, Sumitomo Yuka, Shusuke Yagi, Takashi Iwase, Masashi Akaike and Toshio Matsumoto : Serum Lipid Disorder is Associated with Left Ventricular Diastolic Dysfunction in Elderly Individuals, 22nd Scientific Meeting of the International Society of Hypertension 2008, Berlin, Germany, Berlin, Jun. 2008.
Ken-ichi Aihara, Takayuki Ise, Sumiko Yoshida, Sumitomo Yuka, Shusuke Yagi, Takashi Iwase, Masashi Akaike and Toshio Matsumoto : The active form of vitamin D, 1,25(OH)2D3, prevents vascular remodeling and glucose intolerance in elderly individuals, 22nd Scientific Meeting of the International Society of Hypertension 2008, Berlin, Germany, Berlin, Jun. 2008.
Takako Miyamoto, Shinsuke Kido, Toshio Matsumoto and Hisaaki Taniguchi : Proteomic Analysis of Osteoblast Differentiation, 20th IUBMB International Congress of Biochemistry and Molecular Biology and 11th FAOBMB Congress, Kyoto, Jul. 2006.
Hirotsugu Kurobe, Yuki Izawa, Y Fukuhara, Tamotsu Kanbara, A Kurushima, Ken-ichi Aihara, Masashi Akaike, Masashi Kano, Takashi Kitaichi, Yutaka Masuda, Hiroyuki Azuma, Toshiaki Tamaki, Toshio Matsumoto, Tetsuya Kitagawa, Shuhei Tomita and Masanori Yoshizumi : HIF-ARNT transcriptional system in Tcells has a pivotal role in vascular inflammation and remodeling, XIL International Symposium on Atherosclerosis, Italy, Jun. 2006.
Yutaka Masuda, H Kurobe, Takashi Kitaichi, Masashi Kano, A Kurushima, Tetsuya Kitagawa, T Iwase, Masashi Akaike, M Abe and Toshio Matsumoto : Erythropoietin induced peripheral stem cell transplantation for severe ischemic limbs, The 14th Annual Meeting of the Asian Society for Cardiovascular Surgery, Osaka, Jun. 2006.
Ken-ichi Aihara, Mihara Masatomo, Hiroyuki Azuma, Masashi Akaike, Takaya Matsushita, Yasumasa Ikeda, Shusuke Yagi, Takashi Iwase, Hashizume Shunji, Fujimura Mitsunori and Toshio Matsumoto : Argatroban, a synthetic thrombin antagonist, can reduce insulin resistance though thrombin inactivation in the db/db mouse model of type 2 diabetes mellitus, XIV International Symposium on Atherosclerosis, 2006 Rome, Italy, Jun. 2006.
Ali Jalili, Shuji Ozaki, Tomoko Hara, Etsuko Sekimoto, Yoichi Tanaka, Takashi Ohshima, Hironobu Shibata, Toshihiro Hashimoto, Masahiro Abe, Yasuhiko Nishioka and Toshio Matsumoto : Generation of HM1.24-specific cytotoxic T lymphocytes from peripheral blood stem cell harvests of patients with multiple myeloma, 46th Annual Meeting: American Society of Hematology, San Francisco, Dec. 2004.
Ken-ichi Aihara, Takamori Nobuyuki, Yasuhiko Kanagawa, Masashi Akaike, Fujimura Mitsunori, Yoshida Tomonori, Hashizume Shunji, Kato Midori, Yasumasa Ikeda, Hiroyuki Azuma and Toshio Matsumoto : Heparin cofactor II is inversely related to the severity of carotid atherosclerosis, American Heart Association, Scientific Sessions 2003 Orland Florida USA, Nov. 2003.
Keiichiro Watanabe, Masahiro Abe, 川谷 誠, Masahiro Hiasa, Shingen Nakamura, Eiji Tanaka, 長田 裕之 and Toshio Matsumoto : リベロマイシンAによる酸性環境がもたらす骨髄腫薬剤耐性の克服と骨病変形成の抑制, The Annual Meeting of the Japanese Society for Bone and Mineral Research Program & Abstracts, 208,
(Keyword)
*Pyrans; *Spiro Compounds; *骨疾患; *骨髄腫; *抗腫瘍剤耐性 / *Reveromycin A
Ashtar Mohannad, Hirofumi Tenshin, Jumpei Teramachi, Masahiro Hiasa, Kotaro Tanimoto, Oda Asuka, Iwasa Masami, Takeshi Harada, Ariunzaya Erdene Bat, Kimiko Sogabe, Oura Masahiro, Shiroh Fujii, Kumiko Kagawa, Shingen Nakamura, Hirokazu Miki, Eiji Tanaka, Toshio Matsumoto and Masahiro Abe : Roles of ROS in induction of bone disease and cancer treatment-induced bone loss in myeloma., The 80th Annual Meeting of the Japanese Society of Hematology, Oct. 2018.
Kotaro Tanimoto, Masahiro Hiasa, Hirofumi Tenshin, Jumpei Teramachi, Oda Asuka, Mohannad Ashtar, Ariunzaya Bat-Erdene, Iwasa Masami, Kimiko Sogabe, Oura Masahiro, Takeshi Harada, Shingen Nakamura, Hirokazu Miki, Itsuro Endo, Eiji Tanaka, Toshio Matsumoto and Masahiro Abe : Impact of denervation-induced paralysis and mechanical unloading on tumor expansion in myeloma., The 80th Annual Meeting of the Japanese Society of Hematology, Oct. 2018.
Masahiro Hiasa, Jumpei Teramachi, Hirofumi Tenshin, Kotaro Tanimoto, Ariunzaya Bat-Erdene, Mohannad Ashtar, Masami Iwasa, Takeshi Harada, Shingen Nakamura, Hirokazu Miki, Kimiko Sogabe, Oura Masahiro, Shiroh Fujii, Kumiko Kagawa, Oda Asuka, Itsuro Endo, Eiji Tanaka, Toshio Matsumoto and Masahiro Abe : The effects of cathepsin K inhibition on osteocytes: its role in bone restoration in MM bone disease., The 80th Annual Meeting of the Japanese Society of Hematology, Oct. 2018.
Jumpei Teramachi, Hirofumi Tenshin, Masahiro Hiasa, Itsuro Endo, Toshio Matsumoto and Masahiro Abe : TAK1 inhibition impairs myeloma cell-bone marrow interaction to reduce myeloma growth and bone destruction, The Annual Meeting of the Japanese Society for Bone and Mineral Research Program & Abstracts, Jul. 2018.
Hirofumi Tenshin, Jumpei Teramachi, 小田 明日香, Ryota Amachi, Masahiro Hiasa, Keiichiro Watanabe, Ariunzaya Baterdene, Masami Iwasa, Shiroh Fujii, Kumiko Kagawa, Shingen Nakamura, Hirokazu Miki, Itsuro Endo, Eiji Tanaka, Toshio Matsumoto and Masahiro Abe : TRAILは破骨細胞を活性化させるが，TAK1阻害により骨髄腫細胞とともに破骨細胞にもTRAILのアポトーシス誘導活性が惹起できる, The 35th Annual Meeting of the Japanese Society for Bone and Mineral Research (oral talk), Jul. 2017.
Jumpei Teramachi, Hiroshi Mori, Yasuo Ochi, Ryota Amachi, Asuka Oda, Masahiro Hiasa, Takeshi Harada, Shiroh Fujii, Shingen Nakamura, Hirokazu Miki, Kumiko Kagawa, Itsuro Endo, Eiji Tanaka, Toshio Matsumoto and Masahiro Abe : Potent induction of bone formation by anti-resorptive cathepsin K inhibitor in myeloma., The 77th Annual Meeting of the Japanese Society of Hematology, Oct. 2016.
Jumpei Teramachi, Masahiro Hiasa, 小田 明日香, Hirofumi Tenshin, Ryota Amachi, 原田 武志, Keiichiro Watanabe, Shingen Nakamura, Hirokazu Miki, Itsuro Endo, Tatsuji Haneji, Toshio Matsumoto and Masahiro Abe : 骨髄腫腫瘍進展と骨破壊病変形成におけるTAK1-Pim-2経路の役割, The Annual Meeting of the Japanese Society for Bone and Mineral Research Program & Abstracts, Jul. 2016.
Ryota Amachi, Masahiro Hiasa, Jumpei Teramachi, A Oda, Hirofumi Tenshin, Keiichiro Watanabe, Shingen Nakamura, H Miki, Kumiko Kagawa, Shiroh Fujii, Eiji Tanaka, Toshio Matsumoto and Masahiro Abe : Mechanism of the TRPV1 up-regulatation in myeloma cells and adaptation to an acidic microenvironment, 第77回日本血液学会学術集会, Oct. 2015.
Keiichiro Watanabe, Jumpei Teramachi, H Mori, Y Ochi, Ryota Amachi, A Oda, Masahiro Hiasa, T Harada, Shiroh Fujii, Shingen Nakamura, H Miki, Kumiko Kagawa, Itsuro Endo, Eiji Tanaka, Toshio Matsumoto and Masahiro Abe : Potent induction of bone formation by anti-resorptive cathepsin K inhibitor in myeloma, 第77回日本血液学会学術集会, Oct. 2015.
Jumpei Teramachi, Masahiro Hiasa, 小田 明日香, Hirofumi Tenshin, Ryota Amachi, Shingen Nakamura, Hirokazu Miki, Itsuro Endo, Tatsuji Haneji, Toshio Matsumoto and Masahiro Abe : Pim阻害による骨髄種骨病変の治療:破骨細胞形成の抑制, The Annual Meeting of the Japanese Society for Bone and Mineral Research Program & Abstracts, Jul. 2015.
Jumpei Teramachi, Masahiro Hiasa, 小田 明日香, Hirofumi Tenshin, Ryota Amachi, Shingen Nakamura, Hirokazu Miki, Itsuro Endo, Tatsuji Haneji, Toshio Matsumoto and Masahiro Abe : 骨髄腫腫瘍進展と骨破壊病変形成における TAK-1の枢軸的役割, The Annual Meeting of the Japanese Society for Bone and Mineral Research Program & Abstracts, Jul. 2015.
Ryota Amachi, Masahiro Hiasa, Jumpei Teramachi, 小田 明日香, Keiichiro Watanabe, Hirofumi Tenshin, Shingen Nakamura, Hirokazu Miki, Itsuro Endo, Takeshi Kondo, Eiji Tanaka, Toshio Matsumoto and Masahiro Abe : 酸性環境での骨髄腫細胞のTRPV1の発現亢進と酸環境への適応, The Annual Meeting of the Japanese Society for Bone and Mineral Research Program & Abstracts, 165, Jul. 2015.
Hirofumi Tenshin, Jumpei Teramachi, 小田 明日香, Ryota Amachi, Masahiro Hiasa, Keiichiro Watanabe, Shingen Nakamura, Hirokazu Miki, Itsuro Endo, Eiji Tanaka, Toshio Matsumoto and Masahiro Abe : アポトーシス誘導因子TRAILによる破骨細胞分化・生存の促進, The Annual Meeting of the Japanese Society for Bone and Mineral Research Program & Abstracts, 164, Jul. 2015.
Ryota Amachi, Masahiro Hiasa, Keiichiro Watanabe, Jumpei Teramachi, 小田 明日香, Keiichiro Watanabe, Shingen Nakamura, Itsuro Endo, Eiji Tanaka, Toshio Matsumoto and Masahiro Abe : 酸が惹起する骨髄腫細胞の酸感受と生存シグナルの悪循環, The Annual Meeting of the Japanese Society for Bone and Mineral Research Program & Abstracts, 225, Jul. 2014.
Keiichiro Watanabe, Masahiro Abe, H Mori, K Udaka, M Iwasa, D Hanson, Ryota Amachi, Masahiro Hiasa, T Harada, Shiroh Fujii, Shingen Nakamura, H Miki, Kumiko Kagawa, Itsuro Endo, Eiji Tanaka and Toshio Matsumoto : Bone restoration and tumor suppression in myeloma by cathepsin K inhibition with Bortezomib, 第75回日本血液学会学術集会, Oct. 2013.
Ryota Amachi, Keiichiro Watanabe, Shiroh Fujii, T Harada, H Miki, S Nakamura, A Oda, Masahiro Hiasa, Eiji Tanaka, Toshio Matsumoto and Masahiro Abe : An acdic milieu confers the resistance to TRAIL in myeloma cells through the PI3K-Akt-mediated epigenetic down-regulation of the TRAIL receptor DR4, International Bone and Mineral Society 2013, May 2013.
Keiichiro Watanabe, Masahiro Abe, H Mori, Ryota Amachi, Masahiro Hiasa, T Harada, Shiroh Fujii, S Nakamura, H Miki, K Kagawa, I Endo, Eiji Tanaka and Toshio Matsumoto : Induction of cathepsin K induce bone formation in myeloma osteolytic lesions, International Bone and Mineral Society 2013, May 2013.
Ryota Amachi, Keiichiro Watanabe, Shiroh Fujii, T Harada, H Miki, S Nakamura, A Oda, Masahiro Hiasa, Eiji Tanaka, Toshio Matsumoto and Masahiro Abe : An acdic milieu suppresses histone acetylation in myeloma cells to down-regulate the TRAIL receptor DR4 expression, 14th International Myeloma Workshop, Apr. 2013.
Keiichiro Watanabe, Masahiro Abe, Ryota Amachi, Masahiro Hiasa, T Harada, Shiroh Fujii, S Nakamura, H Miki, K Kagawa, I Endo, Eiji Tanaka and Toshio Matsumoto : Induction of bone formation in myeloma osteolytic lesions by cathepsin K inhibition, 14th International Myeloma Workshop, Apr. 2013.
Ryota Amachi, Masahiro Abe, Keiichiro Watanabe, Masahiro Hiasa, Eiji Tanaka and Toshio Matsumoto : An acidic milieu suppresses DR4 editing and induces p22 c-FLIP to cause myeloma resistance to TRAIL, 第74回日本血液学会学術集会, Oct. 2012.
Keiichiro Watanabe, Masahiro Abe, Q Cui, Masahiro Hiasa, M Kawatani, T Harada, Shiroh Fujii, Shingen Nakamura, Hirokazu Miki, A Nakano, K Kagawa, K Takeuchi, H Osada, Eiji Tanaka and Toshio Matsumoto : Targeting an acidic microenvironment by reveromycin A to overcome drug resistance to myeloma cells and ameliorate bone disease., 第36回日本骨髄腫研究会総会, Nov. 2011.
Masahiro Hiasa, A Nakano, Keiichiro Watanabe, C Qu, T Harada, S Fujii, H Miki, S Nakamura, K Kagawa, K Takeuchi, Eiji Tanaka, Kenzo Asaoka, Shuji Ozaki, Toshio Matsumoto and Masahiro Abe : Prevention of tumor growth and bone destruction in myeloma by Pim kinase inhibition, Bone Biology Forum, 19-21st Aug, 2011, Shizuoka., Aug. 2011.
Sumiko Yoshida, Ken-ichi Aihara, Takayuki Ise, Yuka Ueda, Yasumasa Ikeda, Takashi Iwase, Masashi Akaike, Masataka Sata and Toshio Matsumoto : A role of androgen receptor in ischemia-induced tissue damage and angiogenesis in male, 第42回日本動脈硬化学会総会・学術集会 長良川国際会議場, Jul. 2010.
Y. Sumiko, Ken-ichi Aihara, T. Ise, Yuka Ueda, Yasumasa Ikeda, Takashi Iwase, Masashi Akaike, Masataka Sata and Toshio Matsumoto : A role of androgen receptor in iscchemia-induced tissue damage and angiogenesis in male., 第42回日本動脈硬化学会総会・学術集会, Jul. 2010.
Sumiko Yoshida, Ken-ichi Aihara, Takayuki Ise, Yuka Ueda, Yasumasa Ikeda, Takashi Iwase, Masashi Akaike, Masataka Sata and Toshio Matsumoto : Accelerated cellular apoptosis and impaired angiogenesis after hindlimb ischemia in male mice lacking androgen receptor, 第74回 日本循環器学会総会・学術集会 国立京都国際会館, Mar. 2010.
Ken-ichi Aihara, Sumiko Yoshida, Takayuki Ise, Sumitomo Yuka, Shusuke Yagi, Takashi Iwase, Kurahashi Kiyoe, Itsuro Endo, Yuichi Fujinaka, Masashi Akaike, Masataka Sata and Toshio Matsumoto : Increased serum triglyceride but not LDL cholesterol is associated with left ventricular diastolic dysfunction., 第73回日本循環器学会総会・学術集会, Mar. 2009.
Tomoyuki Yuasa, Toshiyuki Obata, Ichiro Yokota, Eiji Okamoto, Yoshiko Kanezaki, Hiroshi Maegawa, Fumiko Hirota, Kazuhiro Kishi, Seiichi Hashida, Hisao Nagaya, Ogura Yuko, Masuda Kazuhiko, Mitsuru Matsumoto, Toshio Matsumoto, Atsunori Kashiwagi and Yousuke Ebina : Soluble insulin receptor ectodomain is elevated in the plasma of patients with diabetes., International Symposium on Diabetes - Kickoff of Hannover-Tokushima Research Communiation, Mar. 2009.
Masahiro Hiasa, Masahiro Abe, Kenzo Asaoka and Toshio Matsumoto : inhibition of osteoclastgenesis by ectodomain shedding of M-CSF receptor, 17, Aug. 2008.
Ken-ichi Aihara, Takayuki Ise, Sumiko Yoshida, 住友 由佳, Shusuke Yagi, Takashi Iwase, Masashi Akaike and Toshio Matsumoto : 1α 25 dihydroxyvitamin D3 is a protective factor against vascular remodeling and glucose tolerance in elderly individuals, 第72回日本循環器学会学術集会, Mar. 2008.