{"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/38245883","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=405470","label":"url"}],"paper_title":{"en":"Acute accumulation of PIM2 and NRF2 and recovery of β5 subunit activity mitigate multiple myeloma cell susceptibility to proteasome inhibitors.","ja":"Acute accumulation of PIM2 and NRF2 and recovery of β5 subunit activity mitigate multiple myeloma cell susceptibility to proteasome inhibitors."},"authors":{"en":[{"name":"Sogabe Kimiko"},{"name":"Nakamura Shingen"},{"name":"Higa Yoshiki"},{"name":"Miki Hirokazu"},{"name":"Oda Asuka"},{"name":"Maruhashi Tomoko"},{"name":"Sumitani Ryohei"},{"name":"Oura Masahiro"},{"name":"Takahashi Mamiko"},{"name":"Nakamura Masafumi"},{"name":"Maeda Yusaku"},{"name":"Hara Tomoyo"},{"name":"Yamagami Hiroki"},{"name":"Fujii Shiroh"},{"name":"Kagawa Kumiko"},{"name":"Ozaki Shuji"},{"name":"Kurahashi Kiyoe"},{"name":"Endo Itsuro"},{"name":"Aihara Ken-ichi"},{"name":"Nakaue Emiko"},{"name":"Hiasa Masahiro"},{"name":"Teramachi Jumpei"},{"name":"Harada Takeshi"},{"name":"Abe Masahiro"}],"ja":[{"name":"曽我部 公子"},{"name":"中村 信元"},{"name":"比嘉 佳基"},{"name":"三木 浩和"},{"name":"Oda Asuka"},{"name":"丸橋 朋子"},{"name":"住谷 龍平"},{"name":"大浦 雅博"},{"name":"Takahashi Mamiko"},{"name":"中村 昌史"},{"name":"前田 悠作"},{"name":"原 倫世"},{"name":"山上 紘規"},{"name":"藤井 志朗"},{"name":"賀川 久美子"},{"name":"尾崎 修治"},{"name":"倉橋 清衛"},{"name":"遠藤 逸朗"},{"name":"粟飯原 賢一"},{"name":"中上 絵美子"},{"name":"日浅 雅博"},{"name":"寺町 順平"},{"name":"原田 武志"},{"name":"安倍 正博"}]},"description":{"en":"Resistance to proteasome inhibitors (PIs) has emerged as an important clinical issue. We investigated the mechanisms underlying multiple myeloma (MM) cell resistance to PIs. To mimic their pharmacokinetic/pharmacodynamic (PK/PD) profiles, MM cells were treated with bortezomib and carfilzomib for 1 h at concentrations up to 400 and 1,000 nM, respectively. Susceptibility to these PIs markedly varied among MM cell lines. Pulsatile treatments with PIs suppressed translation, as demonstrated by incorporation of puromycin at 24 h in PI-susceptible MM.1S cells, but not PI-resistant KMS-11 cells. Inhibition of β5 subunit activity decreased at 24 h in KMS-11 cells, even with the irreversible PI carfilzomib, but not under suppression of protein synthesis with cycloheximide. Furthermore, the proteasome-degradable pro-survival factors PIM2 and NRF2 acutely accumulated in MM cells subjected to pulsatile PI treatments. Accumulated NRF2 was trans-localized into the nucleus to induce the expression of its target gene, HMOX1, in MM cells. PIM and Akt inhibition restored the anti-MM effects of PIs, even against PI-resistant KMS-11 cells. Collectively, these results suggest that increased synthesis of β5 proteasome subunit and acute accumulation of PIM2 and NRF2 reduce the anti-MM effects of PIs.","ja":"Resistance to proteasome inhibitors (PIs) has emerged as an important clinical issue. We investigated the mechanisms underlying multiple myeloma (MM) cell resistance to PIs. To mimic their pharmacokinetic/pharmacodynamic (PK/PD) profiles, MM cells were treated with bortezomib and carfilzomib for 1 h at concentrations up to 400 and 1,000 nM, respectively. Susceptibility to these PIs markedly varied among MM cell lines. Pulsatile treatments with PIs suppressed translation, as demonstrated by incorporation of puromycin at 24 h in PI-susceptible MM.1S cells, but not PI-resistant KMS-11 cells. Inhibition of β5 subunit activity decreased at 24 h in KMS-11 cells, even with the irreversible PI carfilzomib, but not under suppression of protein synthesis with cycloheximide. Furthermore, the proteasome-degradable pro-survival factors PIM2 and NRF2 acutely accumulated in MM cells subjected to pulsatile PI treatments. Accumulated NRF2 was trans-localized into the nucleus to induce the expression of its target gene, HMOX1, in MM cells. PIM and Akt inhibition restored the anti-MM effects of PIs, even against PI-resistant KMS-11 cells. Collectively, these results suggest that increased synthesis of β5 proteasome subunit and acute accumulation of PIM2 and NRF2 reduce the anti-MM effects of PIs."},"publication_date":"2024-01-21","publication_name":{"en":"International journal of hematology","ja":"International journal of hematology"},"volume":"Vol.119","number":"No.3","starting_page":"303","ending_page":"315","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1007/s12185-023-03705-9"],"issn":["1865-3774"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/118380","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/37039914","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=395242","label":"url"}],"paper_title":{"en":"Mechanisms of preferential bone formation in myeloma bone lesions by proteasome inhibitors.","ja":"Mechanisms of preferential bone formation in myeloma bone lesions by proteasome inhibitors."},"authors":{"en":[{"name":"Nakaue Emiko"},{"name":"Teramachi Jumpei"},{"name":"Tenshin Hirofumi"},{"name":"Hiasa Masahiro"},{"name":"Harada Takeshi"},{"name":"Oda Asuka"},{"name":"Inoue Yusuke"},{"name":"Shimizu Sou"},{"name":"Higa Yoshiki"},{"name":"Sogabe Kimiko"},{"name":"Oura Masahiro"},{"name":"Hara Tomoyo"},{"name":"Sumitani Ryohei"},{"name":"Maruhashi Tomoko"},{"name":"Yamagami Hiroki"},{"name":"Endo Itsuro"},{"name":"Tanaka Eiji"},{"name":"Abe Masahiro"}],"ja":[{"name":"中上 絵美子"},{"name":"寺町 順平"},{"name":"天眞 寛文"},{"name":"日浅 雅博"},{"name":"原田 武志"},{"name":"Oda Asuka"},{"name":"Inoue Yusuke"},{"name":"清水 宗"},{"name":"比嘉 佳基"},{"name":"曽我部 公子"},{"name":"大浦 雅博"},{"name":"原 倫世"},{"name":"住谷 龍平"},{"name":"Maruhashi Tomoko"},{"name":"山上 紘規"},{"name":"遠藤 逸朗"},{"name":"田中 栄二"},{"name":"安倍 正博"}]},"description":{"en":"Proteasome inhibitors (PIs) can preferentially restore bone in bone-defective lesions of patients with multiple myeloma (MM) who respond favorably to these drugs. Most prior in vitro studies on PIs used continuous exposure to low PI concentrations, although pharmacokinetic analysis in patients has shown that serum concentrations of PIs change in a pulsatile manner. In the present study, we explored the effects of pulsatile treatment with PIs on bone metabolism to simulate in vivo PI pharmacokinetics. Pulsatile treatment with bortezomib, carfilzomib, or ixazomib induced MM cell death but only marginally affected the viability of osteoclasts (OCs) with F-actin ring formation. Pulsatile PI treatment suppressed osteoclastogenesis in OC precursors and bone resorption by mature OCs. OCs robustly enhanced osteoblastogenesis in cocultures with OCs and MC3T3-E1 pre-osteoblastic cells, indicating OC-mediated coupling to osteoblastogenesis. Importantly, pulsatile PI treatment did not impair robust OC-mediated osteoblastogenesis. These results suggest that PIs might sufficiently reduce MM cell-derived osteoblastogenesis inhibitors to permit OC-driven bone formation coupling while suppressing OC differentiation and activity in good responders to PIs. OC-mediated coupling to osteoblastogenesis appears to be a predominant mechanism for preferential occurrence of bone regeneration at sites of osteoclastic bone destruction in good responders.","ja":"Proteasome inhibitors (PIs) can preferentially restore bone in bone-defective lesions of patients with multiple myeloma (MM) who respond favorably to these drugs. Most prior in vitro studies on PIs used continuous exposure to low PI concentrations, although pharmacokinetic analysis in patients has shown that serum concentrations of PIs change in a pulsatile manner. In the present study, we explored the effects of pulsatile treatment with PIs on bone metabolism to simulate in vivo PI pharmacokinetics. Pulsatile treatment with bortezomib, carfilzomib, or ixazomib induced MM cell death but only marginally affected the viability of osteoclasts (OCs) with F-actin ring formation. Pulsatile PI treatment suppressed osteoclastogenesis in OC precursors and bone resorption by mature OCs. OCs robustly enhanced osteoblastogenesis in cocultures with OCs and MC3T3-E1 pre-osteoblastic cells, indicating OC-mediated coupling to osteoblastogenesis. Importantly, pulsatile PI treatment did not impair robust OC-mediated osteoblastogenesis. These results suggest that PIs might sufficiently reduce MM cell-derived osteoblastogenesis inhibitors to permit OC-driven bone formation coupling while suppressing OC differentiation and activity in good responders to PIs. OC-mediated coupling to osteoblastogenesis appears to be a predominant mechanism for preferential occurrence of bone regeneration at sites of osteoclastic bone destruction in good responders."},"publication_date":"2023-04-11","publication_name":{"en":"International Journal of Hematology","ja":"International Journal of Hematology"},"languages":["eng"],"referee":true,"identifiers":{"doi":["10.1007/s12185-023-03601-2"],"issn":["1865-3774"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/118211","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/36129197","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=396173","label":"url"}],"paper_title":{"en":"Novel antimyeloma therapeutic option with inhibition of the HDAC1-IRF4 axis and PIM kinase","ja":"Novel antimyeloma therapeutic option with inhibition of the HDAC1-IRF4 axis and PIM kinase"},"authors":{"en":[{"name":"Harada Takeshi"},{"name":"Ohguchi Hiroto"},{"name":"Oda Asuka"},{"name":"Nakao Michiyasu"},{"name":"Teramachi Jumpei"},{"name":"Hiasa Masahiro"},{"name":"Sumitani Ryohei"},{"name":"Oura Masahiro"},{"name":"Sogabe Kimiko"},{"name":"Maruhashi Tomoko"},{"name":"Takahashi Mamiko"},{"name":"Fujii Shiroh"},{"name":"Nakamura Shingen"},{"name":"Miki Hirokazu"},{"name":"Kagawa Kumiko"},{"name":"Ozaki Shuji"},{"name":"Sano Shigeki"},{"name":"Hideshima Teru"},{"name":"Abe Masahiro"}],"ja":[{"name":"原田 武志"},{"name":"大口 裕人"},{"name":"小田 明日香"},{"name":"中尾 允泰"},{"name":"寺町 順平"},{"name":"日浅 雅博"},{"name":"住谷 龍平"},{"name":"大浦 雅博"},{"name":"曽我部 公子"},{"name":"丸橋 朋子"},{"name":"高橋 真美子"},{"name":"藤井 志朗"},{"name":"中村 信元"},{"name":"三木 浩和"},{"name":"賀川 久美子"},{"name":"尾崎 修治"},{"name":"佐野 茂樹"},{"name":"秀島 輝"},{"name":"安倍 正博"}]},"description":{"en":"Multiple myeloma (MM) preferentially expands and acquires drug resistance in the bone marrow (BM). We herein examined the role of histone deacetylase 1 (HDAC1) in the constitutive activation of the master transcription factor IRF4 and the prosurvival mediator PIM2 kinase in MM cells. The knockdown or inhibition of HDAC1 by the class I HDAC inhibitor MS-275 reduced the basal expression of IRF4 and PIM2 in MM cells. Mechanistically, the inhibition of HDAC1 decreased IRF4 transcription through histone hyperacetylation and inhibiting the recruitment of RNA polymerase II at the IRF4 locus, thereby reducing IRF4-targeting genes, including PIM2. In addition to the transcriptional regulation of PIM2 by the HDAC1-IRF4 axis, PIM2 was markedly upregulated by external stimuli from BM stromal cells and interleukin-6 (IL-6). Upregulated PIM2 contributed to the attenuation of the cytotoxic effects of MS-275. Class I HDAC and PIM kinase inhibitors cooperatively suppressed MM cell growth in the presence of IL-6 and in vivo. Therefore, the present results demonstrate the potential of the simultaneous targeting of the intrinsic HDAC1-IRF4 axis plus externally activated PIM2 as an efficient therapeutic option for MM fostered in the BM.","ja":"Multiple myeloma (MM) preferentially expands and acquires drug resistance in the bone marrow (BM). We herein examined the role of histone deacetylase 1 (HDAC1) in the constitutive activation of the master transcription factor IRF4 and the prosurvival mediator PIM2 kinase in MM cells. The knockdown or inhibition of HDAC1 by the class I HDAC inhibitor MS-275 reduced the basal expression of IRF4 and PIM2 in MM cells. Mechanistically, the inhibition of HDAC1 decreased IRF4 transcription through histone hyperacetylation and inhibiting the recruitment of RNA polymerase II at the IRF4 locus, thereby reducing IRF4-targeting genes, including PIM2. In addition to the transcriptional regulation of PIM2 by the HDAC1-IRF4 axis, PIM2 was markedly upregulated by external stimuli from BM stromal cells and interleukin-6 (IL-6). Upregulated PIM2 contributed to the attenuation of the cytotoxic effects of MS-275. Class I HDAC and PIM kinase inhibitors cooperatively suppressed MM cell growth in the presence of IL-6 and in vivo. Therefore, the present results demonstrate the potential of the simultaneous targeting of the intrinsic HDAC1-IRF4 axis plus externally activated PIM2 as an efficient therapeutic option for MM fostered in the BM."},"publication_date":"2023-03-28","publication_name":{"en":"Blood Advances","ja":"Blood Advances"},"volume":"Vol.7","number":"No.6","starting_page":"1019","ending_page":"1032","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1182/bloodadvances.2022007155"],"issn":["2473-9537"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/36856824","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=395910","label":"url"}],"paper_title":{"en":"Myeloma bone disease: pathogenesis and management in the era of new anti-myeloma agents.","ja":"Myeloma bone disease: pathogenesis and management in the era of new anti-myeloma agents."},"authors":{"en":[{"name":"Teramachi Jumpei"},{"name":"Miki Hirokazu"},{"name":"Nakamura Shingen"},{"name":"Hiasa Masahiro"},{"name":"Harada Takeshi"},{"name":"Abe Masahiro"}],"ja":[{"name":"寺町 順平"},{"name":"三木 浩和"},{"name":"中村 信元"},{"name":"日浅 雅博"},{"name":"原田 武志"},{"name":"安倍 正博"}]},"description":{"en":"MM cells produce a variety of cytokines to stimulate receptor activator of nuclear factor-κB ligand-mediated osteoclastogenesis and suppress osteoblastic differentiation from bone marrow stromal cells, leading to extensive bone destruction with rapid loss of bone. MM cells alter the microenvironment through bone destruction where they colonize, which in turn favors tumor growth and survival, thereby forming a vicious cycle between tumor progression and bone destruction. Denosumab or zoledronic acid is currently recommended to be administered at the start of treatment in newly diagnosed patients with MM with bone disease. Proteasome inhibitors and the anti-CD38 monoclonal antibody daratumumab have been demonstrated to exert bone-modifying activity in responders. Besides their anti-tumor activity, the effects of new anti-MM agents on bone metabolism should be more precisely analyzed in patients with MM. Because prognosis in patients with MM has been significantly improved owing to the implementation of new agents, the therapeutic impact of bone-modifying agents should be re-estimated in the era of these new agents.","ja":"MM cells produce a variety of cytokines to stimulate receptor activator of nuclear factor-κB ligand-mediated osteoclastogenesis and suppress osteoblastic differentiation from bone marrow stromal cells, leading to extensive bone destruction with rapid loss of bone. MM cells alter the microenvironment through bone destruction where they colonize, which in turn favors tumor growth and survival, thereby forming a vicious cycle between tumor progression and bone destruction. Denosumab or zoledronic acid is currently recommended to be administered at the start of treatment in newly diagnosed patients with MM with bone disease. Proteasome inhibitors and the anti-CD38 monoclonal antibody daratumumab have been demonstrated to exert bone-modifying activity in responders. Besides their anti-tumor activity, the effects of new anti-MM agents on bone metabolism should be more precisely analyzed in patients with MM. Because prognosis in patients with MM has been significantly improved owing to the implementation of new agents, the therapeutic impact of bone-modifying agents should be re-estimated in the era of these new agents."},"publication_date":"2023-03-01","publication_name":{"en":"Journal of Bone and Mineral Metabolism","ja":"Journal of Bone and Mineral Metabolism"},"starting_page":"1","ending_page":"16","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1007/s00774-023-01403-4"],"issn":["1435-5604"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/118313","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/36670994","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=395239","label":"url"}],"paper_title":{"en":"The Xanthine Oxidase Inhibitor Febuxostat Suppresses Adipogenesis and Activates Nrf2.","ja":"The Xanthine Oxidase Inhibitor Febuxostat Suppresses Adipogenesis and Activates Nrf2."},"authors":{"en":[{"name":"Higa Yoshiki"},{"name":"Hiasa Masahiro"},{"name":"Tenshin Hirofumi"},{"name":"Nakaue Emiko"},{"name":"Tanaka Mariko"},{"name":"Kim Sooha"},{"name":"Nakagawa Motosumi"},{"name":"Shimizu Sou"},{"name":"Tanimoto Kotaro"},{"name":"Teramachi Jumpei"},{"name":"Harada Takeshi"},{"name":"Oda Asuka"},{"name":"Oura Masahiro"},{"name":"Sogabe Kimiko"},{"name":"Hara Tomoyo"},{"name":"Sumitani Ryohei"},{"name":"Maruhashi Tomoko"},{"name":"Yamagami Hiroki"},{"name":"Endo Itsuro"},{"name":"Matsumoto Toshio"},{"name":"Tanaka Eiji"},{"name":"Abe Masahiro"}],"ja":[{"name":"比嘉 佳基"},{"name":"日浅 雅博"},{"name":"天眞 寛文"},{"name":"中上 絵美子"},{"name":"田中 茉里子"},{"name":"金 秀河"},{"name":"中川 宗純"},{"name":"清水 宗"},{"name":"谷本 幸多朗"},{"name":"寺町 順平"},{"name":"原田 武志"},{"name":"Oda Asuka"},{"name":"大浦 雅博"},{"name":"曽我部 公子"},{"name":"Hara Tomoyo"},{"name":"住谷 龍平"},{"name":"Maruhashi Tomoko"},{"name":"山上 紘規"},{"name":"遠藤 逸朗"},{"name":"松本 俊夫"},{"name":"田中 栄二"},{"name":"安倍 正博"}]},"description":{"en":"Xanthine oxidoreductase (XOR) is a rate-limiting enzyme in purine catabolism that acts as a novel regulator of adipogenesis. In pathological states, xanthine oxidoreductase activity increases to produce excess reactive oxygen species (ROS). The nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical inducer of antioxidants, which is bound and repressed by a kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm. The Keap1-Nrf2 axis appears to be a major mechanism for robust inducible antioxidant defenses. Here, we demonstrate that febuxostat, a xanthine oxidase inhibitor, alleviates the increase in adipose tissue mass in obese mouse models with a high-fat diet or ovariectomy. Febuxostat disrupts in vitro adipocytic differentiation in adipogenic media. Adipocytes appeared at day 7 in absence or presence of febuxostat were 160.8 ± 21.2 vs. 52.5 ± 12.7 (p < 0.01) in 3T3L1 cells, and 126.0 ± 18.7 vs. 55.3 ± 13.4 (p < 0.01) in 10T1/2 cells, respectively. Adipocyte differentiation was further enhanced by the addition of hydrogen peroxide, which was also suppressed by febuxostat. Interestingly, febuxostat, but not allopurinol (another xanthine oxidase inhibitor), rapidly induced the nuclear translocation of Nrf2 and facilitated the degradation of Keap1, similar to the electrophilic Nrf2 activator omaveloxolone. These results suggest that febuxostat alleviates adipogenesis under oxidative conditions, at least in part by suppressing ROS production and Nrf2 activation. Regulation of adipocytic differentiation by febuxostat is expected to inhibit obesity due to menopause or overeating.","ja":"Xanthine oxidoreductase (XOR) is a rate-limiting enzyme in purine catabolism that acts as a novel regulator of adipogenesis. In pathological states, xanthine oxidoreductase activity increases to produce excess reactive oxygen species (ROS). The nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical inducer of antioxidants, which is bound and repressed by a kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm. The Keap1-Nrf2 axis appears to be a major mechanism for robust inducible antioxidant defenses. Here, we demonstrate that febuxostat, a xanthine oxidase inhibitor, alleviates the increase in adipose tissue mass in obese mouse models with a high-fat diet or ovariectomy. Febuxostat disrupts in vitro adipocytic differentiation in adipogenic media. Adipocytes appeared at day 7 in absence or presence of febuxostat were 160.8 ± 21.2 vs. 52.5 ± 12.7 (p < 0.01) in 3T3L1 cells, and 126.0 ± 18.7 vs. 55.3 ± 13.4 (p < 0.01) in 10T1/2 cells, respectively. Adipocyte differentiation was further enhanced by the addition of hydrogen peroxide, which was also suppressed by febuxostat. Interestingly, febuxostat, but not allopurinol (another xanthine oxidase inhibitor), rapidly induced the nuclear translocation of Nrf2 and facilitated the degradation of Keap1, similar to the electrophilic Nrf2 activator omaveloxolone. These results suggest that febuxostat alleviates adipogenesis under oxidative conditions, at least in part by suppressing ROS production and Nrf2 activation. Regulation of adipocytic differentiation by febuxostat is expected to inhibit obesity due to menopause or overeating."},"publication_date":"2023-01-05","publication_name":{"en":"Antioxidants","ja":"Antioxidants"},"volume":"Vol.12","number":"No.1","languages":["eng"],"referee":true,"identifiers":{"doi":["10.3390/antiox12010133"],"issn":["2076-3921"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/117150","label":"url"},{"@id":"https://cir.nii.ac.jp/crid/1390573947533793024/","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=395394","label":"url"}],"paper_title":{"en":"Aberrant upregulation of the endogenous PP2A inhibitor CIP2A is vital for myeloma cell growth and survival","ja":"Aberrant upregulation of the endogenous PP2A inhibitor CIP2A is vital for myeloma cell growth and survival"},"authors":{"en":[{"name":"Shimizu Sou"},{"name":"Teramachi Jumpei"},{"name":"Harada Takeshi"},{"name":"Hiasa Masahiro"},{"name":"Tenshin Hirofumi"},{"name":"Oda A"},{"name":"Seki A"},{"name":"Inoue Y"},{"name":"Tanimoto Kotaro"},{"name":"Higa Yoshiki"},{"name":"Oura M"},{"name":"Sogabe K"},{"name":"Harada Takeshi"},{"name":"Sumitani Ryohei"},{"name":"Maruhashi T"},{"name":"Yamagami H"},{"name":"Sawa Y"},{"name":"Endo Itsuro"},{"name":"Tsuneyama K"},{"name":"Matsumoto Toshio"},{"name":"Tanaka Eiji"},{"name":"Abe Masahiro"}],"ja":[{"name":"清水 宗"},{"name":"寺町 順平"},{"name":"原田 武志"},{"name":"日浅 雅博"},{"name":"天眞 寛文"},{"name":"Oda A"},{"name":"Seki A"},{"name":"Inoue Y"},{"name":"谷本 幸多朗"},{"name":"比嘉 佳基"},{"name":"Oura M"},{"name":"Sogabe K"},{"name":"原田 武志"},{"name":"住谷 龍平"},{"name":"Maruhashi T"},{"name":"Yamagami H"},{"name":"Sawa Y"},{"name":"遠藤 逸朗"},{"name":"Tsuneyama K"},{"name":"松本 俊夫"},{"name":"田中 栄二"},{"name":"安倍 正博"}]},"description":{"en":"
The serine/threonine kinase TAK1 is constitutively overexpressed and auto-phosphorylated in multiple myeloma (MM) cells. Protein phosphatase 2A (PP2A) is a major serine/threonine phosphatase which dephosphorylates proteins phosphorylated by various serine/threonine kinases to regulate multiple cellular functions. We recently reported that the serine/threonine kinase TGF-β-activated kinase-1 (TAK1) is highly expressed and auto-phosphorylated to mediate critical growth and survival signaling in MM cells. We demonstrate here that regulation of PP2A activity inversely affects the phosphorylation levels of TAK1 in MM cells, and that MM cells aberrantly overexpress cancerous inhibitor of PP2A (CIP2A), an endogenous inhibitor for PP2A. CIP2A gene silencing as well as treatment with the CIP2A inhibitor TD52 potently induced MM cell death along with suppression of TAK1 expression in MM cells. These results suggest the critical role of PP2A inactivation via CIP2A upregulation in TAK1 phosphorylation and its protein expression and thereby MM cell growth and survival, posing the CIP2A-PP2A axis as an important therapeutic target.
","ja":"The serine/threonine kinase TAK1 is constitutively overexpressed and auto-phosphorylated in multiple myeloma (MM) cells. Protein phosphatase 2A (PP2A) is a major serine/threonine phosphatase which dephosphorylates proteins phosphorylated by various serine/threonine kinases to regulate multiple cellular functions. We recently reported that the serine/threonine kinase TGF-β-activated kinase-1 (TAK1) is highly expressed and auto-phosphorylated to mediate critical growth and survival signaling in MM cells. We demonstrate here that regulation of PP2A activity inversely affects the phosphorylation levels of TAK1 in MM cells, and that MM cells aberrantly overexpress cancerous inhibitor of PP2A (CIP2A), an endogenous inhibitor for PP2A. CIP2A gene silencing as well as treatment with the CIP2A inhibitor TD52 potently induced MM cell death along with suppression of TAK1 expression in MM cells. These results suggest the critical role of PP2A inactivation via CIP2A upregulation in TAK1 phosphorylation and its protein expression and thereby MM cell growth and survival, posing the CIP2A-PP2A axis as an important therapeutic target.
"},"publication_date":"2022-06-17","publication_name":{"en":"International Journal of Myeloma","ja":"International Journal of Myeloma"},"volume":"Vol.12","number":"No.2","starting_page":"14","ending_page":"23","languages":["eng"],"referee":true,"identifiers":{"doi":["10.57352/ijm.12.2_14"],"issn":["2187-3143"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/116715","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/34788982","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=386812","label":"url"}],"paper_title":{"en":"Mechanical unloading aggravates bone destruction and tumor expansion in myeloma.","ja":"Mechanical unloading aggravates bone destruction and tumor expansion in myeloma."},"authors":{"en":[{"name":"Tanimoto Kotaro"},{"name":"Hiasa Masahiro"},{"name":"Tenshin Hirofumi"},{"name":"Teramachi Jumpei"},{"name":"Oda Asuka"},{"name":"Harada Takeshi"},{"name":"Higa Yoshiki"},{"name":"Sogabe Kimiko"},{"name":"Oura Masahiro"},{"name":"Sumitani Ryohei"},{"name":"Hara Tomoyo"},{"name":"Endo Itsuro"},{"name":"Matsumoto Toshio"},{"name":"Tanaka Eiji"},{"name":"Abe Masahiro"}],"ja":[{"name":"谷本 幸多朗"},{"name":"日浅 雅博"},{"name":"天眞 寛文"},{"name":"寺町 順平"},{"name":"Oda Asuka"},{"name":"原田 武志"},{"name":"比嘉 佳基"},{"name":"曽我部 公子"},{"name":"Oura Masahiro"},{"name":"住谷 龍平"},{"name":"原 倫世"},{"name":"遠藤 逸朗"},{"name":"松本 俊夫"},{"name":"田中 栄二"},{"name":"安倍 正博"}]},"publication_date":"2022-03-01","publication_name":{"en":"Haematologica","ja":"Haematologica"},"volume":"Vol.107","number":"No.3","starting_page":"744","ending_page":"749","languages":["eng"],"referee":true,"identifiers":{"doi":["10.3324/haematol.2021.278295"],"issn":["1592-8721"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/117260","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/35079379","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=386837","label":"url"}],"paper_title":{"en":"TGF-β-activated kinase-1 inhibitor LL-Z1640-2 reduces joint inflammation and bone destruction in mouse models of rheumatoid arthritis by inhibiting NLRP3 inflammasome, TACE, TNF-α and RANKL expression.","ja":"TGF-β-activated kinase-1 inhibitor LL-Z1640-2 reduces joint inflammation and bone destruction in mouse models of rheumatoid arthritis by inhibiting NLRP3 inflammasome, TACE, TNF-α and RANKL expression."},"authors":{"en":[{"name":"Tenshin Hirofumi"},{"name":"Teramachi Jumpei"},{"name":"Ashtar Mohannad"},{"name":"Hiasa Masahiro"},{"name":"Inoue Yusuke"},{"name":"Oda Asuka"},{"name":"Tanimoto Kotaro"},{"name":"Shimizu Sou"},{"name":"Higa Yoshiki"},{"name":"Harada Takeshi"},{"name":"Oura Masahiro"},{"name":"Sogabe Kimiko"},{"name":"Hara Tomoyo"},{"name":"Sumitani Ryohei"},{"name":"Maruhashi Tomoko"},{"name":"Sebe Mayu"},{"name":"Tsutsumi Rie"},{"name":"Sakaue Hiroshi"},{"name":"Endo Itsuro"},{"name":"Matsumoto Toshio"},{"name":"Tanaka Eiji"},{"name":"Abe Masahiro"}],"ja":[{"name":"天眞 寛文"},{"name":"寺町 順平"},{"name":"ASHTAR MOHANNAD"},{"name":"日浅 雅博"},{"name":"井上 雄介"},{"name":"Oda Asuka"},{"name":"谷本 幸多朗"},{"name":"清水 宗"},{"name":"比嘉 佳基"},{"name":"原田 武志"},{"name":"大浦 雅博"},{"name":"曽我部 公子"},{"name":"原 倫世"},{"name":"住谷 龍平"},{"name":"丸橋 朋子"},{"name":"Sebe Mayu"},{"name":"堤 理恵"},{"name":"阪上 浩"},{"name":"遠藤 逸朗"},{"name":"松本 俊夫"},{"name":"田中 栄二"},{"name":"安倍 正博"}]},"description":{"en":"TAK1 inhibition with LLZ may become a novel treatment strategy to effectively alleviate inflammasome-mediated inflammation and RANKL-induced osteoclastic bone destruction in joints alongside its potent suppression of TNF-α and IL-6 production and proteinase-mediated pathological processes in RA.","ja":"TAK1 inhibition with LLZ may become a novel treatment strategy to effectively alleviate inflammasome-mediated inflammation and RANKL-induced osteoclastic bone destruction in joints alongside its potent suppression of TNF-α and IL-6 production and proteinase-mediated pathological processes in RA."},"publication_date":"2022-01-19","publication_name":{"en":"Clinical & translational immunology","ja":"Clinical & translational immunology"},"volume":"Vol.11","number":"No.1","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1002/cti2.1371"],"issn":["2050-0068"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/116529","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/32273474","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=377110","label":"url"}],"paper_title":{"en":"TAK1 is a pivotal therapeutic target for tumor progression and bone destruction in myeloma","ja":"TAK1 is a pivotal therapeutic target for tumor progression and bone destruction in myeloma"},"authors":{"en":[{"name":"Teramachi Jumpei"},{"name":"Tenshin Hirofumi"},{"name":"Hiasa Masahiro"},{"name":"Oda Asuka"},{"name":"Bat-Erdene Ariunzaya"},{"name":"Harada Takeshi"},{"name":"Nakamura Shingen"},{"name":"Ashtar Mohannad"},{"name":"Shimizu Sou"},{"name":"Iwasa Masami"},{"name":"Sogabe Kimiko"},{"name":"Oura Masahiro"},{"name":"Fujii Shiroh"},{"name":"Kagawa Kumiko"},{"name":"Miki Hirokazu"},{"name":"Endo Itsuro"},{"name":"Haneji Tatsuji"},{"name":"Matsumoto Toshio"},{"name":"Abe Masahiro"}],"ja":[{"name":"寺町 順平"},{"name":"天眞 寛文"},{"name":"日浅 雅博"},{"name":"小田 明日香"},{"name":"Ariunzaya Bat-Erdene"},{"name":"原田 武志"},{"name":"中村 信元"},{"name":"ASHTAR MOHANNAD"},{"name":"清水 宗"},{"name":"岩佐 昌美"},{"name":"曽我部 公子"},{"name":"大浦 雅博"},{"name":"藤井 志朗"},{"name":"賀川 久美子"},{"name":"三木 浩和"},{"name":"遠藤 逸朗"},{"name":"羽地 達次"},{"name":"松本 俊夫"},{"name":"安倍 正博"}]},"description":{"en":"Along with the tumor progression, the bone marrow microenvironment is skewed in multiple myeloma (MM), which underlies the unique pathophysiology of MM and confers aggressiveness and drug resistance in MM cells. TGF-β-activated kinase-1 (TAK1) mediates a wide range of intracellular signaling pathways. We demonstrate here that TAK1 is constitutively overexpressed and phosphorylated in MM cells, and that TAK1 inhibition suppresses the activation of NF-κB, p38MAPK, ERK and STAT3 to decrease the expression of critical mediators for MM growth and survival, including PIM2, MYC, Mcl-1, IRF4, and Sp1, along with a substantial reduction in the angiogenic factor VEGF in MM cells. Intriguingly, TAK1 phosphorylation was also induced along with upregulation of vascular cell adhesion molecule-1 (VCAM-1) in bone marrow stromal cells (BMSCs) in cocultures with MM cells, which facilitated MM cell-BMSC adhesion while inducing IL-6 production and receptor activator of nuclear factor κ-Β ligand (RANKL) expression by BMSCs. TAK1 inhibition effectively impaired MM cell adhesion to BMSCs to disrupt the support of MM cell growth and survival by BMSCs. Furthermore, TAK1 inhibition suppressed osteoclastogenesis enhanced by RANKL in cocultures of bone marrow cells with MM cells, and restored osteoblastic differentiation suppressed by MM cells or inhibitory factors for osteoblastogenesis overproduced in MM. Finally, treatment with the TAK1 inhibitor LLZ1640-2 markedly suppressed MM tumor growth and prevented bone destruction and loss in mouse MM models. Therefore, TAK1 inhibition may be a promising therapeutic option targeting not only MM cells but also the skewed bone marrow microenvironment in MM.","ja":"Along with the tumor progression, the bone marrow microenvironment is skewed in multiple myeloma (MM), which underlies the unique pathophysiology of MM and confers aggressiveness and drug resistance in MM cells. TGF-β-activated kinase-1 (TAK1) mediates a wide range of intracellular signaling pathways. We demonstrate here that TAK1 is constitutively overexpressed and phosphorylated in MM cells, and that TAK1 inhibition suppresses the activation of NF-κB, p38MAPK, ERK and STAT3 to decrease the expression of critical mediators for MM growth and survival, including PIM2, MYC, Mcl-1, IRF4, and Sp1, along with a substantial reduction in the angiogenic factor VEGF in MM cells. Intriguingly, TAK1 phosphorylation was also induced along with upregulation of vascular cell adhesion molecule-1 (VCAM-1) in bone marrow stromal cells (BMSCs) in cocultures with MM cells, which facilitated MM cell-BMSC adhesion while inducing IL-6 production and receptor activator of nuclear factor κ-Β ligand (RANKL) expression by BMSCs. TAK1 inhibition effectively impaired MM cell adhesion to BMSCs to disrupt the support of MM cell growth and survival by BMSCs. Furthermore, TAK1 inhibition suppressed osteoclastogenesis enhanced by RANKL in cocultures of bone marrow cells with MM cells, and restored osteoblastic differentiation suppressed by MM cells or inhibitory factors for osteoblastogenesis overproduced in MM. Finally, treatment with the TAK1 inhibitor LLZ1640-2 markedly suppressed MM tumor growth and prevented bone destruction and loss in mouse MM models. Therefore, TAK1 inhibition may be a promising therapeutic option targeting not only MM cells but also the skewed bone marrow microenvironment in MM."},"publication_date":"2021-05-01","publication_name":{"en":"Haematologica","ja":"Haematologica"},"volume":"Vol.106","number":"No.5","starting_page":"1401","ending_page":"1413","languages":["eng"],"referee":true,"identifiers":{"doi":["10.3324/haematol.2019.234476"],"issn":["1592-8721"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/115041","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/32283857","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=365352","label":"url"}],"paper_title":{"en":"The Roles of ROS Generation in RANKL-Induced Osteoclastogenesis: Suppressive Effects of Febuxostat.","ja":"The Roles of ROS Generation in RANKL-Induced Osteoclastogenesis: Suppressive Effects of Febuxostat."},"authors":{"en":[{"name":"Ashtar Mohannad"},{"name":"Tenshin Hirofumi"},{"name":"Teramachi Jumpei"},{"name":"Bat-Erdene Ariunzaya"},{"name":"Hiasa Masahiro"},{"name":"Oda Asuka"},{"name":"Tanimoto Kotaro"},{"name":"Shimizu Sou"},{"name":"Higa Yoshiki"},{"name":"Harada Takeshi"},{"name":"Oura Masahiro"},{"name":"Sogabe Kimiko"},{"name":"Nakamura Shingen"},{"name":"Fujii Shiroh"},{"name":"Sumitani Ryohei"},{"name":"Miki Hirokazu"},{"name":"Udaka Kengo"},{"name":"Takahashi Mamiko"},{"name":"Kagawa Kumiko"},{"name":"Endo Itsuro"},{"name":"Tanaka Eiji"},{"name":"Matsumoto Toshio"},{"name":"Abe Masahiro"}],"ja":[{"name":"ASHTAR MOHANNAD"},{"name":"天眞 寛文"},{"name":"寺町 順平"},{"name":"Ariunzaya Bat-Erdene"},{"name":"日浅 雅博"},{"name":"Oda Asuka"},{"name":"谷本 幸多朗"},{"name":"清水 宗"},{"name":"比嘉 佳基"},{"name":"原田 武志"},{"name":"大浦 雅博"},{"name":"曽我部 公子"},{"name":"中村 信元"},{"name":"藤井 志朗"},{"name":"住谷 龍平"},{"name":"三木 浩和"},{"name":"宇髙 憲吾"},{"name":"Takahashi Mamiko"},{"name":"賀川 久美子"},{"name":"遠藤 逸朗"},{"name":"田中 栄二"},{"name":"松本 俊夫"},{"name":"安倍 正博"}]},"description":{"en":"Receptor activator of NF-κB ligand (RANKL), a critical mediator of osteoclastogenesis, is upregulated in multiple myeloma (MM). The xanthine oxidase inhibitor febuxostat, clinically used for prevention of tumor lysis syndrome, has been demonstrated to effectively inhibit not only the generation of uric acid but also the formation of reactive oxygen species (ROS). ROS has been demonstrated to mediate RANKL-mediated osteoclastogenesis. In the present study, we therefore explored the role of cancer-treatment-induced ROS in RANKL-mediated osteoclastogenesis and the suppressive effects of febuxostat on ROS generation and osteoclastogenesis. RANKL dose-dependently induced ROS production in RAW264.7 preosteoclastic cells; however, febuxostat inhibited the RANKL-induced ROS production and osteoclast (OC) formation. Interestingly, doxorubicin (Dox) further enhanced RANKL-induced osteoclastogenesis through upregulation of ROS production, which was mostly abolished by addition of febuxostat. Febuxostat also inhibited osteoclastogenesis enhanced in cocultures of bone marrow cells with MM cells. Importantly, febuxostat rather suppressed MM cell viability and did not compromise Dox's anti-MM activity. In addition, febuxostat was able to alleviate pathological osteoclastic activity and bone loss in ovariectomized mice. Collectively, these results suggest that excessive ROS production by aberrant RANKL overexpression and/or anticancer treatment disadvantageously impacts bone, and that febuxostat can prevent the ROS-mediated osteoclastic bone damage.","ja":"Receptor activator of NF-κB ligand (RANKL), a critical mediator of osteoclastogenesis, is upregulated in multiple myeloma (MM). The xanthine oxidase inhibitor febuxostat, clinically used for prevention of tumor lysis syndrome, has been demonstrated to effectively inhibit not only the generation of uric acid but also the formation of reactive oxygen species (ROS). ROS has been demonstrated to mediate RANKL-mediated osteoclastogenesis. In the present study, we therefore explored the role of cancer-treatment-induced ROS in RANKL-mediated osteoclastogenesis and the suppressive effects of febuxostat on ROS generation and osteoclastogenesis. RANKL dose-dependently induced ROS production in RAW264.7 preosteoclastic cells; however, febuxostat inhibited the RANKL-induced ROS production and osteoclast (OC) formation. Interestingly, doxorubicin (Dox) further enhanced RANKL-induced osteoclastogenesis through upregulation of ROS production, which was mostly abolished by addition of febuxostat. Febuxostat also inhibited osteoclastogenesis enhanced in cocultures of bone marrow cells with MM cells. Importantly, febuxostat rather suppressed MM cell viability and did not compromise Dox's anti-MM activity. In addition, febuxostat was able to alleviate pathological osteoclastic activity and bone loss in ovariectomized mice. Collectively, these results suggest that excessive ROS production by aberrant RANKL overexpression and/or anticancer treatment disadvantageously impacts bone, and that febuxostat can prevent the ROS-mediated osteoclastic bone damage."},"publication_date":"2020-04-09","publication_name":{"en":"Cancers","ja":"Cancers"},"volume":"Vol.12","number":"No.4","languages":["eng"],"referee":true,"identifiers":{"doi":["10.3390/cancers12040929"],"issn":["2072-6694"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/31372589","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=356144","label":"url"}],"paper_title":{"en":"Persistent Activation of Calcium-Sensing Receptor Suppresses Bone Turnover, Increases Microcracks, and Decreases Bone Strength.","ja":"Persistent Activation of Calcium-Sensing Receptor Suppresses Bone Turnover, Increases Microcracks, and Decreases Bone Strength."},"authors":{"en":[{"name":"Bingzi Dong"},{"name":"Endo Itsuro"},{"name":"Yukoyo Ohnishi"},{"name":"Yukari Mitsui"},{"name":"Kurahashi Kiyoe"},{"name":"Kanai Mai"},{"name":"Hiasa Masahiro"},{"name":"Teramachi Jumpei"},{"name":"Tenshin Hirofumi"},{"name":"Fukumoto Seiji"},{"name":"Abe Masahiro"},{"name":"Matsumoto Toshio"}],"ja":[{"name":"Bingzi Dong"},{"name":"遠藤 逸朗"},{"name":"大西 幸代"},{"name":"三井 由加里"},{"name":"倉橋 清衛"},{"name":"金井 麻衣"},{"name":"日浅 雅博"},{"name":"寺町 順平"},{"name":"天眞 寛文"},{"name":"福本 誠二"},{"name":"安倍 正博"},{"name":"松本 俊夫"}]},"description":{"en":"Activating mutations of calcium-sensing receptor (CaSR) cause autosomal dominant hypocalcemia type 1 (ADH1). Patients with ADH1 exhibit similar features to patients with hypoparathyroidism, including reduced serum parathyroid hormone (PTH) and Ca with low bone turnover. Although persistent suppression of bone turnover may increase bone fragility, bone strength in ADH1 patients has been unclear. We created knock-in mice harboring the A843E activating mutation of CaSR, mimicking severe features of ADH1 patients. The severe form of ADH1 model mice showed smaller body and bone size with lower bone mineral density (BMD) and cortical area of the femur compared with age-matched wild-type (WT) mice. Bone strength in the femur was lower in ADH1 mice even after correction by bone geometry and/or BMD. Microcracks were markedly increased in ADH1 mice, but were rarely detected in WT mice. There was a negative correlation between bone strength corrected by bone geometry and/or BMD and microcrack number or density in ADH1 and WT mice. Among ADH1 mice, negative correlation was still observed between bone strength and microcrack number or density. Microcracks increased with age in ADH1 mice, and were negatively correlated with bone strength. Treatment with PTH(1-34) or a calcilytic, JTT-305, increased bone turnover, reduced microcracks, and increased bone strength to similar levels to those in WT mice. The increase in microcracks was associated with a reduction in bone strength in ADH1 mice, and aging aggravates these changes. These results demonstrate that activating mutation of CaSR causes reduction in PTH secretion with suppressed bone turnover, that reduced bone turnover is associated with an age-dependent increase in microcracks with a reduction in bone strength, and that both PTH(1-34) and calcilytic ameliorate all these changes in bone turnover and strength. It is suggested that fracture susceptibility may be increased in severe types of ADH1 patients especially in the elderly. © 2019 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.","ja":"Activating mutations of calcium-sensing receptor (CaSR) cause autosomal dominant hypocalcemia type 1 (ADH1). Patients with ADH1 exhibit similar features to patients with hypoparathyroidism, including reduced serum parathyroid hormone (PTH) and Ca with low bone turnover. Although persistent suppression of bone turnover may increase bone fragility, bone strength in ADH1 patients has been unclear. We created knock-in mice harboring the A843E activating mutation of CaSR, mimicking severe features of ADH1 patients. The severe form of ADH1 model mice showed smaller body and bone size with lower bone mineral density (BMD) and cortical area of the femur compared with age-matched wild-type (WT) mice. Bone strength in the femur was lower in ADH1 mice even after correction by bone geometry and/or BMD. Microcracks were markedly increased in ADH1 mice, but were rarely detected in WT mice. There was a negative correlation between bone strength corrected by bone geometry and/or BMD and microcrack number or density in ADH1 and WT mice. Among ADH1 mice, negative correlation was still observed between bone strength and microcrack number or density. Microcracks increased with age in ADH1 mice, and were negatively correlated with bone strength. Treatment with PTH(1-34) or a calcilytic, JTT-305, increased bone turnover, reduced microcracks, and increased bone strength to similar levels to those in WT mice. The increase in microcracks was associated with a reduction in bone strength in ADH1 mice, and aging aggravates these changes. These results demonstrate that activating mutation of CaSR causes reduction in PTH secretion with suppressed bone turnover, that reduced bone turnover is associated with an age-dependent increase in microcracks with a reduction in bone strength, and that both PTH(1-34) and calcilytic ameliorate all these changes in bone turnover and strength. It is suggested that fracture susceptibility may be increased in severe types of ADH1 patients especially in the elderly. © 2019 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research."},"publication_date":"2019-03-06","publication_name":{"en":"JBMR Plus","ja":"JBMR Plus"},"volume":"Vol.3","number":"No.7","starting_page":"e10182","ending_page":"e10182","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1002/jbm4.10182"],"issn":["2473-4039"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/113393","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/30474853","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85057280798&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=348588","label":"url"}],"paper_title":{"en":"Class 1 HDAC and HDAC6 inhibition inversely regulates CD38 induction in myeloma cells via interferon-α and ATRA.","ja":"Class 1 HDAC and HDAC6 inhibition inversely regulates CD38 induction in myeloma cells via interferon-α and ATRA."},"authors":{"en":[{"name":"Bat-Erdene Ariunzaya"},{"name":"Nakamura Shingen"},{"name":"Oda Asuka"},{"name":"Iwasa Masami"},{"name":"Teramachi Jumpei"},{"name":"Ashtar Mohannad"},{"name":"Harada Takeshi"},{"name":"Miki Hirokazu"},{"name":"Tenshin Hirofumi"},{"name":"Hiasa Masahiro"},{"name":"Fujii Shiroh"},{"name":"Sogabe Kimiko"},{"name":"Oura Masahiro"},{"name":"Udaka Kengo"},{"name":"Kagawa Kumiko"},{"name":"Yoshida Sumiko"},{"name":"Aihara Ken-ichi"},{"name":"Kurahashi Kiyoe"},{"name":"Endo Itsuro"},{"name":"Abe Masahiro"}],"ja":[{"name":"Bat-Erdene Ariunzaya"},{"name":"中村 信元"},{"name":"Oda Asuka"},{"name":"Iwasa Masami"},{"name":"寺町 順平"},{"name":"Ashtar Mohannad"},{"name":"原田 武志"},{"name":"三木 浩和"},{"name":"天眞 寛文"},{"name":"日浅 雅博"},{"name":"藤井 志朗"},{"name":"曽我部 公子"},{"name":"大浦 雅博"},{"name":"Udaka Kengo"},{"name":"賀川 久美子"},{"name":"吉田 守美子"},{"name":"粟飯原 賢一"},{"name":"倉橋 清衛"},{"name":"遠藤 逸朗"},{"name":"安倍 正博"}]},"publication_date":"2018-11-26","publication_name":{"en":"British Journal of Haematology","ja":"British Journal of Haematology"},"languages":["eng"],"referee":true,"identifiers":{"doi":["10.1111/bjh.15673"],"issn":["1365-2141"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/112935","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/27748523","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=321702","label":"url"}],"paper_title":{"en":"Pim-2 is a critical target for treatment of osteoclastogenesis enhanced in myeloma.","ja":"Pim-2 is a critical target for treatment of osteoclastogenesis enhanced in myeloma."},"authors":{"en":[{"name":"Teramachi Jumpei"},{"name":"Hiasa Masahiro"},{"name":"Oda Asuka"},{"name":"Harada Takeshi"},{"name":"Nakamura Shingen"},{"name":"Amachi Ryota"},{"name":"Tenshin Hirofumi"},{"name":"Iwasa Masami"},{"name":"Fujii Shiroh"},{"name":"Kagawa Kumiko"},{"name":"Miki Hirokazu"},{"name":"Kurahashi Kiyoe"},{"name":"Yoshida Sumiko"},{"name":"Endo Itsuro"},{"name":"Haneji Tatsuji"},{"name":"Matsumoto Toshio"},{"name":"Abe Masahiro"}],"ja":[{"name":"寺町 順平"},{"name":"日浅 雅博"},{"name":"Oda Asuka"},{"name":"Harada Takeshi"},{"name":"中村 信元"},{"name":"天知 良太"},{"name":"天眞 寛文"},{"name":"Iwasa Masami"},{"name":"藤井 志朗"},{"name":"賀川 久美子"},{"name":"三木 浩和"},{"name":"倉橋 清衛"},{"name":"吉田 守美子"},{"name":"遠藤 逸朗"},{"name":"羽地 達次"},{"name":"松本 俊夫"},{"name":"安倍 正博"}]},"publication_date":"2018-02-17","publication_name":{"en":"British Journal of Haematology","ja":"British Journal of Haematology"},"volume":"Vol.180","number":"No.4","starting_page":"581","ending_page":"585","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1111/bjh.14388"],"issn":["1365-2141"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/112752","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/29327347","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85040344893&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=341053","label":"url"}],"paper_title":{"en":"Unique anti-myeloma activity by thiazolidine-2,4-dione compounds with Pim inhibiting activity.","ja":"Unique anti-myeloma activity by thiazolidine-2,4-dione compounds with Pim inhibiting activity."},"authors":{"en":[{"name":"Fujii Shiroh"},{"name":"Nakamura Shingen"},{"name":"Oda Asuka"},{"name":"Miki Hirokazu"},{"name":"Tenshin Hirofumi"},{"name":"Teramachi Jumpei"},{"name":"Hiasa Masahiro"},{"name":"Bat-Erdene Ariunzaya"},{"name":"Maeda Yusaku"},{"name":"Oura Masahiro"},{"name":"Takahashi Mamiko"},{"name":"Iwasa Masami"},{"name":"Endo Itsuro"},{"name":"Yoshida Sumiko"},{"name":"Aihara Ken-ichi"},{"name":"Kurahashi Kiyoe"},{"name":"Harada Takeshi"},{"name":"Kagawa Kumiko"},{"name":"Nakao Michiyasu"},{"name":"Sano Shigeki"},{"name":"Abe Masahiro"}],"ja":[{"name":"藤井 志朗"},{"name":"中村 信元"},{"name":"Oda Asuka"},{"name":"三木 浩和"},{"name":"天眞 寛文"},{"name":"寺町 順平"},{"name":"日浅 雅博"},{"name":"Bat-Erdene Ariunzaya"},{"name":"Maeda Yusaku"},{"name":"大浦 雅博"},{"name":"Takahashi Mamiko"},{"name":"Iwasa Masami"},{"name":"遠藤 逸朗"},{"name":"吉田 守美子"},{"name":"粟飯原 賢一"},{"name":"倉橋 清衛"},{"name":"原田 武志"},{"name":"賀川 久美子"},{"name":"中尾 允泰"},{"name":"佐野 茂樹"},{"name":"安倍 正博"}]},"description":{"en":"Proviral Integrations of Moloney virus 2 (PIM2) is overexpressed in multiple myeloma (MM) cells, and regarded as an important therapeutic target. Here, we aimed to validate the therapeutic efficacy of different types of PIM inhibitors against MM cells for their possible clinical application. Intriguingly, the thiazolidine-2,4-dione-family compounds SMI-16a and SMI-4a reduced PIM2 protein levels and impaired MM cell survival preferentially in acidic conditions, in contrast to other types of PIM inhibitors, including AZD1208, CX-6258 and PIM447. SMI-16a also suppressed the drug efflux function of breast cancer resistance protein, minimized the sizes of side populations and reduced in vitro colony-forming capacity and in vivo tumourigenic activity in MM cells, suggesting impairment of their clonogenic capacity. PIM2 is known to be subject to ubiquitination-independent proteasomal degradation. Consistent with this, the proteasome inhibitors bortezomib and carfilzomib increased PIM2 protein levels in MM cells without affecting its mRNA levels. However, SMI-16a mitigated the PIM2 protein increase and cooperatively enhanced anti-MM effects in combination with carfilzomib. Collectively, the thiazolidine-2,4-dione-family compounds SMI-16a and SMI-4a uniquely reduce PIM2 protein in MM cells, which may contribute to their profound efficacy in addition to their immediate kinase inhibition. Their combination with proteasome inhibitors is envisioned.","ja":"Proviral Integrations of Moloney virus 2 (PIM2) is overexpressed in multiple myeloma (MM) cells, and regarded as an important therapeutic target. Here, we aimed to validate the therapeutic efficacy of different types of PIM inhibitors against MM cells for their possible clinical application. Intriguingly, the thiazolidine-2,4-dione-family compounds SMI-16a and SMI-4a reduced PIM2 protein levels and impaired MM cell survival preferentially in acidic conditions, in contrast to other types of PIM inhibitors, including AZD1208, CX-6258 and PIM447. SMI-16a also suppressed the drug efflux function of breast cancer resistance protein, minimized the sizes of side populations and reduced in vitro colony-forming capacity and in vivo tumourigenic activity in MM cells, suggesting impairment of their clonogenic capacity. PIM2 is known to be subject to ubiquitination-independent proteasomal degradation. Consistent with this, the proteasome inhibitors bortezomib and carfilzomib increased PIM2 protein levels in MM cells without affecting its mRNA levels. However, SMI-16a mitigated the PIM2 protein increase and cooperatively enhanced anti-MM effects in combination with carfilzomib. Collectively, the thiazolidine-2,4-dione-family compounds SMI-16a and SMI-4a uniquely reduce PIM2 protein in MM cells, which may contribute to their profound efficacy in addition to their immediate kinase inhibition. Their combination with proteasome inhibitors is envisioned."},"publication_date":"2018-01","publication_name":{"en":"British Journal of Haematology","ja":"British Journal of Haematology"},"volume":"Vol.180","number":"No.2","starting_page":"246","ending_page":"258","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1111/bjh.15033"],"issn":["1365-2141"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/29128580","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85033794901&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=339607","label":"url"}],"paper_title":{"en":"Reduction of protein phosphatase 2A Ca promotes in vivo bone formation and adipocyte differentiation.","ja":"Reduction of protein phosphatase 2A Ca promotes in vivo bone formation and adipocyte differentiation."},"authors":{"en":[{"name":"Yoshida Kaya"},{"name":"Teramachi Jumpei"},{"name":"Uchibe Kenta"},{"name":"Ikegame Mika"},{"name":"Qiu Lihong"},{"name":"Yang Di"},{"name":"Okamura Hirohiko"}],"ja":[{"name":"吉田 賀弥"},{"name":"寺町 順平"},{"name":"Uchibe Kenta"},{"name":"Ikegame Mika"},{"name":"Qiu Lihong"},{"name":"楊 諦"},{"name":"岡村 裕彦"}]},"description":{"en":"Serine/threonine protein phosphatase 2A (PP2A) regulates diverse physiological processes such as cell cycle, growth, apoptosis, and signal transduction. Previously, we demonstrated that silencing of the α-isoform of PP2A catalytic subunit (PP2A Cα) in osteoblasts accelerated osteoblast differentiation, whereas its overexpression suppressed differentiation. In this study, we examined the role of PP2A Cα in in vivo bone formation by generating transgenic mice (PP2A-Tg), in which the dominant negative form of PP2A Cα was specifically expressed in osteoblasts. PP2A-Tg mice exhibited an increase in body weight, cortical bone mineral density, and cortical bone thickness. Interestingly, they also displayed higher amounts of adipose tissue in the bone marrow of tibiae. The co-culture study showed that PP2A Cα-knockdown osteoblasts stimulated adipocyte differentiation from undifferentiated mesenchymal cells via upregulation of the adipocyte marker genes, such as peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein α (C/EBPα). These results indicated that the reduction of PP2A Cα levels in osteoblasts promoted bone formation in vivo. Additionally, PP2A Cα in osteoblasts was also potentially involved in controlling adipocyte differentiation through a paracrine mechanism.","ja":"Serine/threonine protein phosphatase 2A (PP2A) regulates diverse physiological processes such as cell cycle, growth, apoptosis, and signal transduction. Previously, we demonstrated that silencing of the α-isoform of PP2A catalytic subunit (PP2A Cα) in osteoblasts accelerated osteoblast differentiation, whereas its overexpression suppressed differentiation. In this study, we examined the role of PP2A Cα in in vivo bone formation by generating transgenic mice (PP2A-Tg), in which the dominant negative form of PP2A Cα was specifically expressed in osteoblasts. PP2A-Tg mice exhibited an increase in body weight, cortical bone mineral density, and cortical bone thickness. Interestingly, they also displayed higher amounts of adipose tissue in the bone marrow of tibiae. The co-culture study showed that PP2A Cα-knockdown osteoblasts stimulated adipocyte differentiation from undifferentiated mesenchymal cells via upregulation of the adipocyte marker genes, such as peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein α (C/EBPα). These results indicated that the reduction of PP2A Cα levels in osteoblasts promoted bone formation in vivo. Additionally, PP2A Cα in osteoblasts was also potentially involved in controlling adipocyte differentiation through a paracrine mechanism."},"publication_date":"2018","publication_name":{"en":"Molecular and Cellular Endocrinology","ja":"Molecular and Cellular Endocrinology"},"volume":"Vol.470","starting_page":"251","ending_page":"258","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.mce.2017.11.005"],"issn":["1872-8057"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/113059","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/29535808","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85041952629&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=339730","label":"url"}],"paper_title":{"en":"Effective impairment of myeloma cells and their progenitors by hyperthermia.","ja":"Effective impairment of myeloma cells and their progenitors by hyperthermia."},"authors":{"en":[{"name":"Miki Hirokazu"},{"name":"Nakamura Shingen"},{"name":"Oda Asuka"},{"name":"Tenshin Hirofumi"},{"name":"Teramachi Jumpei"},{"name":"Hiasa Masahiro"},{"name":"Bat-Erdene Ariunzaya"},{"name":"Maeda Yusaku"},{"name":"Oura Masahiro"},{"name":"Takahashi Mamiko"},{"name":"Iwasa Masami"},{"name":"Harada Takeshi"},{"name":"Fujii Shiroh"},{"name":"Kurahashi Kiyoe"},{"name":"Yoshida Sumiko"},{"name":"Kagawa Kumiko"},{"name":"Endo Itsuro"},{"name":"Kenichi Aihara"},{"name":"Ikuo Mariko"},{"name":"Itou Kouji"},{"name":"Hayashi Koichiro"},{"name":"Nakamura Michihiro"},{"name":"Abe Masahiro"}],"ja":[{"name":"三木 浩和"},{"name":"中村 信元"},{"name":"Oda Asuka"},{"name":"天眞 寛文"},{"name":"寺町 順平"},{"name":"日浅 雅博"},{"name":"Bat-Erdene Ariunzaya"},{"name":"Maeda Yusaku"},{"name":"大浦 雅博"},{"name":"Takahashi Mamiko"},{"name":"Iwasa Masami"},{"name":"原田 武志"},{"name":"藤井 志朗"},{"name":"倉橋 清衛"},{"name":"吉田 守美子"},{"name":"賀川 久美子"},{"name":"遠藤 逸朗"},{"name":"Kenichi Aihara"},{"name":"幾尾 真理子"},{"name":"伊藤 孝司"},{"name":"林 幸壱朗"},{"name":"中村 教泰"},{"name":"安倍 正博"}]},"description":{"en":"Multiple myeloma (MM) remains incurable, and MM-initiating cells or MM progenitors are considered to contribute to disease relapse through their drug-resistant nature. In order to improve the therapeutic efficacy for MM, we recently developed novel superparamagnetic nanoparticles which selectively accumulate in MM tumors and extirpate them by heat generated with magnetic resonance. We here aimed to clarify the therapeutic effects on MM cells and their progenitors by hyperthermia. Heat treatment at 43°C time-dependently induced MM cell death. The treatment upregulated endoplasmic reticulum (ER) stress mediators, ATF4 and CHOP, while reducing the protein levels of Pim-2, IRF4, c-Myc and Mcl-1. Combination with the proteasome inhibitor bortezomib further enhanced ER stress to potentiate MM cell death. The Pim inhibitor SMI-16a also enhanced the reduction of the Pim-2-driven survival factors, IRF4 and c-Myc, in combination with the heat treatment. The heat treatment almost completely eradicated \"side population\" fractions in RPMI8226 and KMS-11 cells and suppressed their clonogenic capacity as determined by colony formation and tumorigenic capacity in SCID mice. These results collectively demonstrated that hyperthermia is able to impair clonogenic drug-resistant fractions of MM cells and enhance their susceptibility to chemotherapeutic drugs.","ja":"Multiple myeloma (MM) remains incurable, and MM-initiating cells or MM progenitors are considered to contribute to disease relapse through their drug-resistant nature. In order to improve the therapeutic efficacy for MM, we recently developed novel superparamagnetic nanoparticles which selectively accumulate in MM tumors and extirpate them by heat generated with magnetic resonance. We here aimed to clarify the therapeutic effects on MM cells and their progenitors by hyperthermia. Heat treatment at 43°C time-dependently induced MM cell death. The treatment upregulated endoplasmic reticulum (ER) stress mediators, ATF4 and CHOP, while reducing the protein levels of Pim-2, IRF4, c-Myc and Mcl-1. Combination with the proteasome inhibitor bortezomib further enhanced ER stress to potentiate MM cell death. The Pim inhibitor SMI-16a also enhanced the reduction of the Pim-2-driven survival factors, IRF4 and c-Myc, in combination with the heat treatment. The heat treatment almost completely eradicated \"side population\" fractions in RPMI8226 and KMS-11 cells and suppressed their clonogenic capacity as determined by colony formation and tumorigenic capacity in SCID mice. These results collectively demonstrated that hyperthermia is able to impair clonogenic drug-resistant fractions of MM cells and enhance their susceptibility to chemotherapeutic drugs."},"publication_date":"2017-11-15","publication_name":{"en":"Oncotarget","ja":"Oncotarget"},"volume":"Vol.9","number":"No.12","starting_page":"10307","ending_page":"10316","languages":["eng"],"referee":true,"identifiers":{"doi":["10.18632/oncotarget.23121"],"issn":["1949-2553"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/111724","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/29296860","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=336276","label":"url"}],"paper_title":{"en":"TAK1 inhibition subverts the osteoclastogenic action of TRAIL while potentiating its antimyeloma effects.","ja":"TAK1 inhibition subverts the osteoclastogenic action of TRAIL while potentiating its antimyeloma effects."},"authors":{"en":[{"name":"Tenshin Hirofumi"},{"name":"Teramachi Jumpei"},{"name":"Oda Asuka"},{"name":"Amachi Ryota"},{"name":"Hiasa Masahiro"},{"name":"Bat-Erdene Ariunzaya"},{"name":"Watanabe Keiichiro"},{"name":"Iwasa Masami"},{"name":"Harada Takeshi"},{"name":"Fujii Shiroh"},{"name":"Kagawa Kumiko"},{"name":"Sogabe Kimiko"},{"name":"Nakamura Shingen"},{"name":"Miki Hirokazu"},{"name":"Kurahashi Kiyoe"},{"name":"Yoshida Sumiko"},{"name":"Aihara Kenichi"},{"name":"Endo Itsuro"},{"name":"Tanaka Eiji"},{"name":"Matsumoto Toshio"},{"name":"Abe Masahiro"}],"ja":[{"name":"天眞 寛文"},{"name":"寺町 順平"},{"name":"Oda Asuka"},{"name":"天知 良太"},{"name":"日浅 雅博"},{"name":"Ariunzaya Bat-Erdene"},{"name":"渡邉 佳一郎"},{"name":"岩佐 昌美"},{"name":"原田 武志"},{"name":"藤井 志朗"},{"name":"賀川 久美子"},{"name":"曽我部 公子"},{"name":"中村 信元"},{"name":"三木 浩和"},{"name":"倉橋 清衛"},{"name":"吉田 守美子"},{"name":"Aihara Kenichi"},{"name":"遠藤 逸朗"},{"name":"田中 栄二"},{"name":"松本 俊夫"},{"name":"安倍 正博"}]},"description":{"en":"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.","ja":"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."},"publication_date":"2017-10-26","publication_name":{"en":"Blood Advances","ja":"Blood Advances"},"volume":"Vol.1","number":"No.24","starting_page":"2124","ending_page":"2137","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1182/bloodadvances.2017008813"],"issn":["2473-9529"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/117742","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/28241467","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=323167","label":"url"}],"paper_title":{"en":"Role of Protein Phosphatase 2A in Osteoblast Differentiation and Function.","ja":"Role of Protein Phosphatase 2A in Osteoblast Differentiation and Function."},"authors":{"en":[{"name":"Okamura Hirohiko"},{"name":"Yoshida Kaya"},{"name":"Morimoto Hiroyuki"},{"name":"Teramachi Jumpei"},{"name":"Ochiai Kazuhiko"},{"name":"Haneji Tatsuji"},{"name":"Yamamoto Akihito"}],"ja":[{"name":"岡村 裕彦"},{"name":"吉田 賀弥"},{"name":"森本 景之"},{"name":"寺町 順平"},{"name":"落合 和彦"},{"name":"羽地 達次"},{"name":"山本 朗仁"}]},"description":{"en":"The reversible phosphorylation of proteins plays hugely important roles in a variety of cellular processes, such as differentiation, proliferation, and apoptosis. These processes are strictly controlled by protein kinases (phosphorylation) and phosphatases (de-phosphorylation). Here we provide a brief history of the study of protein phosphorylation, including a summary of different types of protein kinases and phosphatases. One of the most physiologically important serine/threonine phosphatases is PP2A. This review provides a description of the phenotypes of various PP2A transgenic mice and further focuses on the known functions of PP2A in bone formation, including its role in osteoblast differentiation and function. A reduction in PP2A promotes bone formation and osteoblast differentiation through the regulation of bone-related transcription factors such as Osterix. Interestingly, downregulation of PP2A also stimulates adipocyte differentiation from undifferentiated mesenchymal cells under the appropriate adipogenic differentiation conditions. In osteoblasts, PP2A is also involved in the ability to control osteoclastogenesis as well as in the proliferation and metastasis of osteosarcoma cells. Thus, PP2A is considered to be a comprehensive factor in controlling the differentiation and function of cells derived from mesenchymal cells such as osteoblasts and adipocytes.","ja":"The reversible phosphorylation of proteins plays hugely important roles in a variety of cellular processes, such as differentiation, proliferation, and apoptosis. These processes are strictly controlled by protein kinases (phosphorylation) and phosphatases (de-phosphorylation). Here we provide a brief history of the study of protein phosphorylation, including a summary of different types of protein kinases and phosphatases. One of the most physiologically important serine/threonine phosphatases is PP2A. This review provides a description of the phenotypes of various PP2A transgenic mice and further focuses on the known functions of PP2A in bone formation, including its role in osteoblast differentiation and function. A reduction in PP2A promotes bone formation and osteoblast differentiation through the regulation of bone-related transcription factors such as Osterix. Interestingly, downregulation of PP2A also stimulates adipocyte differentiation from undifferentiated mesenchymal cells under the appropriate adipogenic differentiation conditions. In osteoblasts, PP2A is also involved in the ability to control osteoclastogenesis as well as in the proliferation and metastasis of osteosarcoma cells. Thus, PP2A is considered to be a comprehensive factor in controlling the differentiation and function of cells derived from mesenchymal cells such as osteoblasts and adipocytes."},"publication_date":"2017-02-23","publication_name":{"en":"Journal of Clinical Medicine","ja":"Journal of Clinical Medicine"},"volume":"Vol.6","number":"No.3","languages":["eng"],"referee":true,"invited":true,"identifiers":{"doi":["10.3390/jcm6030023"],"issn":["2077-0383"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/28000855","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=326856","label":"url"}],"paper_title":{"en":"Involvement of interleukin23 induced by Porphyromonas endodontalis lipopolysaccharide in osteoclastogenesis","ja":"Involvement of interleukin23 induced by Porphyromonas endodontalis lipopolysaccharide in osteoclastogenesis"},"authors":{"en":[{"name":"Ma Nan"},{"name":"Yang Di"},{"name":"Okamura Hirohiko"},{"name":"Teramachi Jumpei"},{"name":"Hasegawa Tomokazu"},{"name":"Qiu Lihong"},{"name":"Haneji Tatsuji"}],"ja":[{"name":"Ma Nan"},{"name":"Yang Di"},{"name":"岡村 裕彦"},{"name":"寺町 順平"},{"name":"長谷川 智一"},{"name":"Qiu Lihong"},{"name":"羽地 達次"}]},"description":{"en":"Periapical lesions are characterized by the destruction of periapical bone, and occur as a result of local inflammatory responses to root canal infection by microorganisms including Porphyromonas endodontalis (P. endodontalis). P. endodontalis and its primary virulence factor, lipopolysaccharide (LPS), are associated with the development of periapical lesions and alveolar bone loss. Interleukin-23 (IL-23) is critical in the initiation and progression of periodontal disease via effects on peripheral bone metabolism. The present study investigated the expression of IL-23 in tissue where a periapical lesion was present, and the effect of P. endodontalis LPS on the expression of IL-23 in periodontal ligament (PDL) cells. Reverse transcription- quantitative polymerase chain reaction and immunohistochemistry revealed increased levels of IL-23 expression in tissue with periapical lesions compared with healthy PDL tissue. Treatment with P. endodontalis LPS increased the expression of IL-23 in the SH-9 human PDL cell line. BAY11-7082, a nuclear factor κB inhibitor, suppressed P. endodontalis LPS-induced IL-23 expression in SH-9 cells. Treatment of RAW264.7 cells with conditioned medium from P. endodontalis LPS-treated SH-9 cells promoted osteoclastogenesis. By contrast, RAW264.7 cells treated with conditioned medium from IL-23-knockdown SH-9 cells underwent reduced levels of osteoclastogenesis. The results of the present study indicated that the expression of IL-23 in PDL cells induced by P. endodontalis LPS treatment may be involved in the progression of periapical lesions via stimulation of the osteoclastogenesis process.","ja":"Periapical lesions are characterized by the destruction of periapical bone, and occur as a result of local inflammatory responses to root canal infection by microorganisms including Porphyromonas endodontalis (P. endodontalis). P. endodontalis and its primary virulence factor, lipopolysaccharide (LPS), are associated with the development of periapical lesions and alveolar bone loss. Interleukin-23 (IL-23) is critical in the initiation and progression of periodontal disease via effects on peripheral bone metabolism. The present study investigated the expression of IL-23 in tissue where a periapical lesion was present, and the effect of P. endodontalis LPS on the expression of IL-23 in periodontal ligament (PDL) cells. Reverse transcription- quantitative polymerase chain reaction and immunohistochemistry revealed increased levels of IL-23 expression in tissue with periapical lesions compared with healthy PDL tissue. Treatment with P. endodontalis LPS increased the expression of IL-23 in the SH-9 human PDL cell line. BAY11-7082, a nuclear factor κB inhibitor, suppressed P. endodontalis LPS-induced IL-23 expression in SH-9 cells. Treatment of RAW264.7 cells with conditioned medium from P. endodontalis LPS-treated SH-9 cells promoted osteoclastogenesis. By contrast, RAW264.7 cells treated with conditioned medium from IL-23-knockdown SH-9 cells underwent reduced levels of osteoclastogenesis. The results of the present study indicated that the expression of IL-23 in PDL cells induced by P. endodontalis LPS treatment may be involved in the progression of periapical lesions via stimulation of the osteoclastogenesis process."},"publication_date":"2017-02","publication_name":{"en":"Molecular Medicine Reports","ja":"Molecular Medicine Reports"},"volume":"Vol.15","number":"No.2","starting_page":"559","ending_page":"566","languages":["eng"],"referee":true,"identifiers":{"doi":["10.3892/mmr.2016.6041"],"issn":["1791-3004"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/109988","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/27738323","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=326832","label":"url"}],"paper_title":{"en":"Synergistic targeting of Sp1, a critical transcription factor for myeloma cell growth and survival, by panobinostat and proteasome inhibitors.","ja":"Synergistic targeting of Sp1, a critical transcription factor for myeloma cell growth and survival, by panobinostat and proteasome inhibitors."},"authors":{"en":[{"name":"Bat-Erdene Ariunzaya"},{"name":"Miki Hirokazu"},{"name":"Oda Asuko"},{"name":"Nakamura Shingen"},{"name":"Teramachi Jumpei"},{"name":"Amachi Ryota"},{"name":"Tenshin Hirofumi"},{"name":"Hiasa Masahiro"},{"name":"Iwasa Masami"},{"name":"Harada Takeshi"},{"name":"Fujii Shiroh"},{"name":"Sogabe Kimiko"},{"name":"Kagawa Kumiko"},{"name":"Yoshida Sumiko"},{"name":"Endo Itsuro"},{"name":"Aihara Ken-ichi"},{"name":"Abe Masahiro"}],"ja":[{"name":"Bat-Erdene Ariunzaya"},{"name":"三木 浩和"},{"name":"Oda Asuko"},{"name":"中村 信元"},{"name":"寺町 順平"},{"name":"天知 良太"},{"name":"天眞 寛文"},{"name":"日浅 雅博"},{"name":"Iwasa Masami"},{"name":"原田 武志"},{"name":"藤井 志朗"},{"name":"Sogabe Kimiko"},{"name":"賀川 久美子"},{"name":"吉田 守美子"},{"name":"遠藤 逸朗"},{"name":"粟飯原 賢一"},{"name":"安倍 正博"}]},"description":{"en":"Panobinostat, a pan-deacetylase inhibitor, synergistically elicits cytotoxic activity against myeloma (MM) cells in combination with the proteasome inhibitor bortezomib. Because precise mechanisms for panobinostat's anti-MM action still remain elusive, we aimed to clarify the mechanisms of anti-MM effects of panobinostat and its synergism with proteasome inhibitors. Although the transcription factor Sp1 was overexpressed in MM cells, the Sp1 inhibitor terameprocol induced MM cell death in parallel with reduction of IRF4 and cMyc. Panobinostat induced activation of caspase-8, which was inversely correlated with reduction of Sp1 protein levels in MM cells. The panobinostat-mediated effects were further potentiated to effectively induce MM cell death in combination with bortezomib or carfilzomib even at suboptimal concentrations as a single agent. Addition of the caspase-8 inhibitor z-IETD-FMK abolished the Sp1 reduction not only by panobinostat alone but also by its combination with bortezomib, suggesting caspase-8-mediated Sp1 degradation. The synergistic Sp1 reduction markedly suppressed Sp1-driven prosurvival factors, IRF4 and cMyc. Besides, the combinatory treatment reduced HDAC1, another Sp1 target, in MM cells, which may potentiate HDAC inhibition. Collectively, caspase-8-mediated post-translational Sp1 degradation appears to be among major mechanisms for synergistic anti-MM effects of panobinostat and proteasome inhibitors in combination.","ja":"Panobinostat, a pan-deacetylase inhibitor, synergistically elicits cytotoxic activity against myeloma (MM) cells in combination with the proteasome inhibitor bortezomib. Because precise mechanisms for panobinostat's anti-MM action still remain elusive, we aimed to clarify the mechanisms of anti-MM effects of panobinostat and its synergism with proteasome inhibitors. Although the transcription factor Sp1 was overexpressed in MM cells, the Sp1 inhibitor terameprocol induced MM cell death in parallel with reduction of IRF4 and cMyc. Panobinostat induced activation of caspase-8, which was inversely correlated with reduction of Sp1 protein levels in MM cells. The panobinostat-mediated effects were further potentiated to effectively induce MM cell death in combination with bortezomib or carfilzomib even at suboptimal concentrations as a single agent. Addition of the caspase-8 inhibitor z-IETD-FMK abolished the Sp1 reduction not only by panobinostat alone but also by its combination with bortezomib, suggesting caspase-8-mediated Sp1 degradation. The synergistic Sp1 reduction markedly suppressed Sp1-driven prosurvival factors, IRF4 and cMyc. Besides, the combinatory treatment reduced HDAC1, another Sp1 target, in MM cells, which may potentiate HDAC inhibition. Collectively, caspase-8-mediated post-translational Sp1 degradation appears to be among major mechanisms for synergistic anti-MM effects of panobinostat and proteasome inhibitors in combination."},"publication_date":"2016-11-29","publication_name":{"en":"Oncotarget","ja":"Oncotarget"},"volume":"Vol.7","number":"No.48","starting_page":"79064","ending_page":"79075","languages":["eng"],"referee":true,"identifiers":{"doi":["10.18632/oncotarget.12594"],"issn":["1949-2553"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/113048","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/27626482","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=323181","label":"url"}],"paper_title":{"en":"A vicious cycle between acid sensing and survival signaling in myeloma cells: acid-induced epigenetic alteration.","ja":"A vicious cycle between acid sensing and survival signaling in myeloma cells: acid-induced epigenetic alteration."},"authors":{"en":[{"name":"Amachi Ryota"},{"name":"Hiasa Masahiro"},{"name":"Teramachi Jumpei"},{"name":"Harada Takeshi"},{"name":"Oda Asuka"},{"name":"Nakamura Shingen"},{"name":"Hanson Derek"},{"name":"Watanabe Keiichiro"},{"name":"Fujii Shiroh"},{"name":"Miki Hirokazu"},{"name":"Kagawa Kumiko"},{"name":"Iwasa Masami"},{"name":"Endo Itsuro"},{"name":"Kondo Takeshi"},{"name":"Yoshida Sumiko"},{"name":"Aihara Ken-ichi"},{"name":"Kurahashi Kiyoe"},{"name":"Kuroda Yoshiaki"},{"name":"Horikawa Hideaki"},{"name":"Tanaka Eiji"},{"name":"Abe Masahiro"},{"name":"Matsumoto Toshio"}],"ja":[{"name":"天知 良太"},{"name":"日浅 雅博"},{"name":"寺町 順平"},{"name":"原田 武志"},{"name":"小田 明日香"},{"name":"中村 信元"},{"name":"Derek James Hanson"},{"name":"渡邉 佳一郎"},{"name":"藤井 志朗"},{"name":"三木 浩和"},{"name":"賀川 久美子"},{"name":"岩佐 昌美"},{"name":"遠藤 逸朗"},{"name":"近藤 剛史"},{"name":"吉田 守美子"},{"name":"粟飯原 賢一"},{"name":"倉橋 清衛"},{"name":"黒田 芳明"},{"name":"堀川 秀昌"},{"name":"田中 栄二"},{"name":"安倍 正博"},{"name":"松本 俊夫"}]},"description":{"en":"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.","ja":"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."},"publication_date":"2016-10-25","publication_name":{"en":"Oncotarget","ja":"Oncotarget"},"volume":"Vol.7","number":"No.43","starting_page":"70447","ending_page":"70461","languages":["eng"],"referee":true,"identifiers":{"doi":["10.18632/oncotarget.11927"],"issn":["1949-2553"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/27698446","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=326829","label":"url"}],"paper_title":{"en":"Expansion of Th1-like V9V2T cells by new-generation IMiDs, lenalidomide and pomalidomide, in combination with zoledronic acid.","ja":"Expansion of Th1-like V9V2T cells by new-generation IMiDs, lenalidomide and pomalidomide, in combination with zoledronic acid."},"authors":{"en":[{"name":"Harada Takeshi"},{"name":"Miki Hirokazu"},{"name":"Cui Q"},{"name":"Oda A"},{"name":"Amachi Ryota"},{"name":"Teramachi Jumpei"},{"name":"Bat-Erdene A"},{"name":"Sogabe K"},{"name":"Iwasa M"},{"name":"Fujii Shiroh"},{"name":"Nakamura Shingen"},{"name":"Kagawa Kumiko"},{"name":"Yoshida Sumiko"},{"name":"Endo I"},{"name":"Aihara Ken-ichi"},{"name":"Ozaki Shuji"},{"name":"Matsumoto Toshio"},{"name":"Abe Masahiro"}],"ja":[{"name":"原田 武志"},{"name":"三木 浩和"},{"name":"Cui Q"},{"name":"Oda A"},{"name":"天知 良太"},{"name":"寺町 順平"},{"name":"Bat-Erdene A"},{"name":"Sogabe K"},{"name":"Iwasa M"},{"name":"藤井 志朗"},{"name":"中村 信元"},{"name":"賀川 久美子"},{"name":"吉田 守美子"},{"name":"Endo I"},{"name":"粟飯原 賢一"},{"name":"尾崎 修治"},{"name":"松本 俊夫"},{"name":"安倍 正博"}]},"publication_date":"2016-10-04","publication_name":{"en":"Leukemia","ja":"Leukemia"},"volume":"Vol.31","number":"No.1","starting_page":"258","ending_page":"262","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1038/leu.2016.273"],"issn":["1476-5551"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/27617401","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=320452","label":"url"}],"paper_title":{"en":"Protein phosphatase 2A Cα regulates proliferation, migration, and metastasis of osteosarcoma cells.","ja":"Protein phosphatase 2A Cα regulates proliferation, migration, and metastasis of osteosarcoma cells."},"authors":{"en":[{"name":"Yang Di"},{"name":"Okamura Hirohiko"},{"name":"Morimoto Hiroyuki"},{"name":"Teramachi Jumpei"},{"name":"Haneji Tatsuji"}],"ja":[{"name":"楊 諦"},{"name":"岡村 裕彦"},{"name":"森本 景之"},{"name":"寺町 順平"},{"name":"羽地 達次"}]},"description":{"en":"Osteosarcoma is the most frequent primary bone tumor. Serine/threonine protein phosphatase 2A (PP2A) participates in regulating many important physiological processes, such as cell cycle, growth, apoptosis, and signal transduction. In this study, we examined the expression and function of PP2A Cα in osteosarcoma cells. PP2A Cα expression was expected to be higher in malignant osteosarcoma tissues. PP2A Cα expression level and PP2A activity was higher in malignant osteosarcoma LM8 cells compared with that in primary osteoblasts and in the osteoblast-like cell line MC3T3-E1. Okadaic acid, an inhibitor of PP2A, reduced cell viability and induced apoptosis in LM8 cells. PP2A Cα-knockdown LM8 cells (shPP2A) exhibited less striking filopodial and lamellipodial structures than that in original LM8 cells. Focal adhesion kinase phosphorylation and NF-κB activity decreased in shPP2A-treated cells. Sensitivity to serum deprivation-induced apoptosis increased in shPP2A-treated cells, accompanied by a lower expression level of anti-apoptotic BCL-2 in these cells. Reduction of PP2A Cα resulted in a decrease in the migration ability of LM8 cells in vitro. Reduction in PP2A Cα levels in vivo suppressed proliferation and metastasis in LM8 cells. PP2A Cα expression was also higher in human osteosarcoma MG63 and SaOS-2 cells than that in primary osteoblasts and MC3T3-E1 cells, and reduction in PP2A Cα levels suppressed the cell proliferation rate and migration ability of MG63 cells. These results indicate that PP2A Cα has a critical role in the proliferation and metastasis of osteosarcoma cells; therefore, its inhibition could potentially suppress the malignancy of osteosarcoma cells.","ja":"Osteosarcoma is the most frequent primary bone tumor. Serine/threonine protein phosphatase 2A (PP2A) participates in regulating many important physiological processes, such as cell cycle, growth, apoptosis, and signal transduction. In this study, we examined the expression and function of PP2A Cα in osteosarcoma cells. PP2A Cα expression was expected to be higher in malignant osteosarcoma tissues. PP2A Cα expression level and PP2A activity was higher in malignant osteosarcoma LM8 cells compared with that in primary osteoblasts and in the osteoblast-like cell line MC3T3-E1. Okadaic acid, an inhibitor of PP2A, reduced cell viability and induced apoptosis in LM8 cells. PP2A Cα-knockdown LM8 cells (shPP2A) exhibited less striking filopodial and lamellipodial structures than that in original LM8 cells. Focal adhesion kinase phosphorylation and NF-κB activity decreased in shPP2A-treated cells. Sensitivity to serum deprivation-induced apoptosis increased in shPP2A-treated cells, accompanied by a lower expression level of anti-apoptotic BCL-2 in these cells. Reduction of PP2A Cα resulted in a decrease in the migration ability of LM8 cells in vitro. Reduction in PP2A Cα levels in vivo suppressed proliferation and metastasis in LM8 cells. PP2A Cα expression was also higher in human osteosarcoma MG63 and SaOS-2 cells than that in primary osteoblasts and MC3T3-E1 cells, and reduction in PP2A Cα levels suppressed the cell proliferation rate and migration ability of MG63 cells. These results indicate that PP2A Cα has a critical role in the proliferation and metastasis of osteosarcoma cells; therefore, its inhibition could potentially suppress the malignancy of osteosarcoma cells."},"publication_date":"2016-10","publication_name":{"en":"Laboratory Investigation; a Journal of Technical Methods and Pathology","ja":"Laboratory Investigation; a Journal of Technical Methods and Pathology"},"volume":"Vol.96","number":"No.10","starting_page":"1050","ending_page":"1062","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1038/labinvest.2016.82"],"issn":["1530-0307"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/26878170","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84959912039&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=307921","label":"url"}],"paper_title":{"en":"Measles virus nucleocapsid protein increases osteoblast differentiation in Paget's disease.","ja":"Measles virus nucleocapsid protein increases osteoblast differentiation in Paget's disease."},"authors":{"en":[{"name":"Teramachi Jumpei"},{"name":"Nagata Yuki"},{"name":"Mohammad Khalid"},{"name":"Inagaki Yuji"},{"name":"Ohata Yasuhisa"},{"name":"Guise Theresa"},{"name":"Michou Laëtitia"},{"name":"Brown Jacques P"},{"name":"Windle Jolene J"},{"name":"Kurihara Noriyoshi"},{"name":"Roodman G David"}],"ja":[{"name":"寺町 順平"},{"name":"Nagata Yuki"},{"name":"Mohammad Khalid"},{"name":"稲垣 裕司"},{"name":"Ohata Yasuhisa"},{"name":"Guise Theresa"},{"name":"Michou Laëtitia"},{"name":"Brown Jacques P"},{"name":"Windle Jolene J"},{"name":"Kurihara Noriyoshi"},{"name":"Roodman G David"}]},"description":{"en":"Paget's disease (PD) is characterized by focal and dramatic bone resorption and formation. Treatments that target osteoclasts (OCLs) block both pagetic bone resorption and formation; therefore, PD offers key insights into mechanisms that couple bone resorption and formation. Here, we evaluated OCLs from 3 patients with PD and determined that measles virus nucleocapsid protein (MVNP) was expressed in 70% of these OCLs. Moreover, transgenic mice with OCL-specific expression of MVNP (MVNP mice) developed PD-like bone lesions that required MVNP-dependent induction of high IL-6 expression levels in OCLs. In contrast, mice harboring a knockin of p62P394L (p62-KI mice), which is the most frequent PD-associated mutation, exhibited increased bone resorption, but not formation. Evaluation of OCLs from MVNP, p62-KI, and WT mice revealed increased IGF1 expression in MVNP-expressing OCLs that resulted from the high IL-6 expression levels in these cells. IL-6, in turn, increased the expression of coupling factors, specifically ephrinB2 on OCLs and EphB4 on osteoblasts (OBs). IGF1 enhanced ephrinB2 expression on OCLs and OB differentiation. Importantly, ephrinB2 and IGF1 levels were increased in MVNP-expressing OCLs from patients with PD and MVNP-transduced human OCLs compared with levels detected in controls. Further, anti-IGF1 or anti-IGF1R blocked Runx2 and osteocalcin upregulation in OBs cocultured with MVNP-expressing OCLs. These results suggest that in PD, MVNP upregulates IL-6 and IGF1 in OCLs to increase ephrinB2-EphB4 coupling and bone formation.","ja":"Paget's disease (PD) is characterized by focal and dramatic bone resorption and formation. Treatments that target osteoclasts (OCLs) block both pagetic bone resorption and formation; therefore, PD offers key insights into mechanisms that couple bone resorption and formation. Here, we evaluated OCLs from 3 patients with PD and determined that measles virus nucleocapsid protein (MVNP) was expressed in 70% of these OCLs. Moreover, transgenic mice with OCL-specific expression of MVNP (MVNP mice) developed PD-like bone lesions that required MVNP-dependent induction of high IL-6 expression levels in OCLs. In contrast, mice harboring a knockin of p62P394L (p62-KI mice), which is the most frequent PD-associated mutation, exhibited increased bone resorption, but not formation. Evaluation of OCLs from MVNP, p62-KI, and WT mice revealed increased IGF1 expression in MVNP-expressing OCLs that resulted from the high IL-6 expression levels in these cells. IL-6, in turn, increased the expression of coupling factors, specifically ephrinB2 on OCLs and EphB4 on osteoblasts (OBs). IGF1 enhanced ephrinB2 expression on OCLs and OB differentiation. Importantly, ephrinB2 and IGF1 levels were increased in MVNP-expressing OCLs from patients with PD and MVNP-transduced human OCLs compared with levels detected in controls. Further, anti-IGF1 or anti-IGF1R blocked Runx2 and osteocalcin upregulation in OBs cocultured with MVNP-expressing OCLs. These results suggest that in PD, MVNP upregulates IL-6 and IGF1 in OCLs to increase ephrinB2-EphB4 coupling and bone formation."},"publication_date":"2016-02-15","publication_name":{"en":"The Journal of Clinical Investigation","ja":"The Journal of Clinical Investigation"},"volume":"Vol.126","number":"No.3","starting_page":"1012","ending_page":"1022","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1172/JCI82012"],"issn":["1558-8238"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/26795455","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84956688215&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=308366","label":"url"}],"paper_title":{"en":"Histone demethylase Jmjd3 regulates osteoblast apoptosis through targeting anti-apoptotic protein Bcl-2 and pro-apoptotic protein Bim.","ja":"Histone demethylase Jmjd3 regulates osteoblast apoptosis through targeting anti-apoptotic protein Bcl-2 and pro-apoptotic protein Bim."},"authors":{"en":[{"name":"Yang Di"},{"name":"Okamura Hirohiko"},{"name":"Teramachi Jumpei"},{"name":"Haneji Tatsuji"}],"ja":[{"name":"楊 諦"},{"name":"岡村 裕彦"},{"name":"寺町 順平"},{"name":"羽地 達次"}]},"description":{"en":"Posttranslational modifications including histone methylation regulate gene transcription through directly affecting the structure of chromatin. Trimethylation of histone H3K27 (H3K27me3) contributes to gene silencing and the histone demethylase Jumonji domain-containing 3 (Jmjd3) specifically removes the methylation of H3K27me3, followed by the activation of gene expression. In the present study, we explored the roles of Jmjd3 in regulating osteoblast apoptosis. Knockdown of Jmjd3 promoted osteoblast apoptosis induced by serum deprivation with decreased mitochondrial membrane potential and increased levels of caspase-3 activation, PARP cleavage, and DNA fragmentation. B cell lymphoma-2 (Bcl-2), an anti-apoptotic protein, was down-regulated by knockdown of Jmjd3 through retaining H3K27me3 on its promoter region. Knockdown of Jmjd3 increased the pro-apoptotic activity of Bim through inhibiting ERK-dependent phosphorylation of Bim. Protein kinase D1 (PKD1), which stimulates ERK phosphorylation, decreased in the Jmjd3-knockdown cells and introduction of PKD1 relieved osteoblast apoptosis in the Jmjd3-knockdown cells through increasing ERK-regulated Bim phosphorylation. These results suggest that Jmjd3 regulates osteoblast apoptosis through targeting Bcl-2 expression and Bim phosphorylation.","ja":"Posttranslational modifications including histone methylation regulate gene transcription through directly affecting the structure of chromatin. Trimethylation of histone H3K27 (H3K27me3) contributes to gene silencing and the histone demethylase Jumonji domain-containing 3 (Jmjd3) specifically removes the methylation of H3K27me3, followed by the activation of gene expression. In the present study, we explored the roles of Jmjd3 in regulating osteoblast apoptosis. Knockdown of Jmjd3 promoted osteoblast apoptosis induced by serum deprivation with decreased mitochondrial membrane potential and increased levels of caspase-3 activation, PARP cleavage, and DNA fragmentation. B cell lymphoma-2 (Bcl-2), an anti-apoptotic protein, was down-regulated by knockdown of Jmjd3 through retaining H3K27me3 on its promoter region. Knockdown of Jmjd3 increased the pro-apoptotic activity of Bim through inhibiting ERK-dependent phosphorylation of Bim. Protein kinase D1 (PKD1), which stimulates ERK phosphorylation, decreased in the Jmjd3-knockdown cells and introduction of PKD1 relieved osteoblast apoptosis in the Jmjd3-knockdown cells through increasing ERK-regulated Bim phosphorylation. These results suggest that Jmjd3 regulates osteoblast apoptosis through targeting Bcl-2 expression and Bim phosphorylation."},"publication_date":"2016-01-12","publication_name":{"en":"Biochimica et Biophysica Acta (BBA) - Molecular Cell Research","ja":"Biochimica et Biophysica Acta (BBA) - Molecular Cell Research"},"volume":"Vol.1863","number":"No.4","starting_page":"650","ending_page":"659","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.bbamcr.2016.01.006"],"issn":["0167-4889"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/27718290","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=320993","label":"url"}],"paper_title":{"en":"PKR regulates LPS-induced osteoclast formation and bone destruction in vitro and in vivo.","ja":"PKR regulates LPS-induced osteoclast formation and bone destruction in vitro and in vivo."},"authors":{"en":[{"name":"Teramachi Jumpei"},{"name":"Inagaki Yuji"},{"name":"Shinohara Hiroki"},{"name":"Okamura Hirohiko"},{"name":"Yang Di"},{"name":"Ochiai Kazuhiko"},{"name":"Baba Ryoko"},{"name":"Morimoto Hiroyuki"},{"name":"Nagata Toshihiko"},{"name":"Haneji Tatsuji"}],"ja":[{"name":"寺町 順平"},{"name":"稲垣 裕司"},{"name":"Shinohara Hiroki"},{"name":"岡村 裕彦"},{"name":"Yang Di"},{"name":"Ochiai Kazuhiko"},{"name":"Baba Ryoko"},{"name":"森本 景之"},{"name":"永田 俊彦"},{"name":"羽地 達次"}]},"description":{"en":"PKR plays a pivotal role in LPS-induced bone loss in PD, and, thus, has potential as a therapeutic target for PD. This article is protected by copyright. All rights reserved.","ja":"PKR plays a pivotal role in LPS-induced bone loss in PD, and, thus, has potential as a therapeutic target for PD. This article is protected by copyright. All rights reserved."},"publication_date":"2016","publication_name":{"en":"Oral Diseases","ja":"Oral Diseases"},"languages":["eng"],"referee":true,"identifiers":{"doi":["10.1111/odi.12592"],"issn":["1601-0825"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/25920016","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84941105888&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=308365","label":"url"}],"paper_title":{"en":"Histone demethylase Utx regulates differentiation and mineralization in osteoblasts.","ja":"Histone demethylase Utx regulates differentiation and mineralization in osteoblasts."},"authors":{"en":[{"name":"Yang Di"},{"name":"Okamura Hirohiko"},{"name":"Teramachi Jumpei"},{"name":"Haneji Tatsuji"}],"ja":[{"name":"楊 諦"},{"name":"岡村 裕彦"},{"name":"寺町 順平"},{"name":"羽地 達次"}]},"description":{"en":"Alteration of methylation status of lysine 27 on histone H3 (H3K27) associates with dramatic changes in gene expression in response to various differentiation signals. Demethylation of H3K27 is controlled by specific histone demethylases including ubiquitously transcribed tetratricopeptide repeat X chromosome (Utx). However, the role of Utx in osteoblast differentiation remains unknown. In this study, we examined whether Utx should be involved in osteoblast differentiation. Expression of Utx increased during osteoblast differentiation in MC3T3-E1 cells and primary osteoblasts. GSK-J1, a potent inhibitor of H3K27 demethylase, increased the levels of trimethylated H3K27 (H3K27me3) and decreased the expressions of Runx2 and Osterix and ALP activity in MC3T3-E1 cells. Stable knockdown of Utx by shRNA attenuated osteoblast differentiation and decreased ALP activity, calcium content, and bone-related gene expressions. Silencing of Utx increased the level of H3K27me3 on the promoter regions of Runx2 and Osterix and decreased the promoter activities of Runx2 and Osterix. Taken together, our present results propose that Utx plays important roles in osteoblast differentiation by controlling the expressions of Runx2 and Osterix.","ja":"Alteration of methylation status of lysine 27 on histone H3 (H3K27) associates with dramatic changes in gene expression in response to various differentiation signals. Demethylation of H3K27 is controlled by specific histone demethylases including ubiquitously transcribed tetratricopeptide repeat X chromosome (Utx). However, the role of Utx in osteoblast differentiation remains unknown. In this study, we examined whether Utx should be involved in osteoblast differentiation. Expression of Utx increased during osteoblast differentiation in MC3T3-E1 cells and primary osteoblasts. GSK-J1, a potent inhibitor of H3K27 demethylase, increased the levels of trimethylated H3K27 (H3K27me3) and decreased the expressions of Runx2 and Osterix and ALP activity in MC3T3-E1 cells. Stable knockdown of Utx by shRNA attenuated osteoblast differentiation and decreased ALP activity, calcium content, and bone-related gene expressions. Silencing of Utx increased the level of H3K27me3 on the promoter regions of Runx2 and Osterix and decreased the promoter activities of Runx2 and Osterix. Taken together, our present results propose that Utx plays important roles in osteoblast differentiation by controlling the expressions of Runx2 and Osterix."},"publication_date":"2015-11","publication_name":{"en":"Journal of Cellular Biochemistry","ja":"Journal of Cellular Biochemistry"},"volume":"Vol.116","number":"No.11","starting_page":"2628","ending_page":"2636","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1002/jcb.25210"],"issn":["1097-4644"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/109501","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/26384349","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84946086135&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=310845","label":"url"}],"paper_title":{"en":"Effective impairment of myeloma cells and their progenitors by blockade of monocarboxylate transportation.","ja":"Effective impairment of myeloma cells and their progenitors by blockade of monocarboxylate transportation."},"authors":{"en":[{"name":"Hanson Derek James"},{"name":"Nakamura Shingen"},{"name":"Amachi Ryota"},{"name":"Hiasa Masahiro"},{"name":"Oda Asuka"},{"name":"Tsuji Daisuke"},{"name":"Itoh Kohji"},{"name":"Harada Takeshi"},{"name":"Horikawa Kazuki"},{"name":"Teramachi Jumpei"},{"name":"Miki Hirokazu"},{"name":"Matsumoto Toshio"},{"name":"Abe Masahiro"}],"ja":[{"name":"Hanson Derek James"},{"name":"中村 信元"},{"name":"天知 良太"},{"name":"日浅 雅博"},{"name":"Oda Asuka"},{"name":"辻 大輔"},{"name":"Itoh Kohji"},{"name":"Harada Takeshi"},{"name":"堀川 一樹"},{"name":"寺町 順平"},{"name":"三木 浩和"},{"name":"松本 俊夫"},{"name":"安倍 正博"}]},"description":{"en":"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.","ja":"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."},"publication_date":"2015-10-20","publication_name":{"en":"Oncotarget","ja":"Oncotarget"},"volume":"Vol.6","number":"No.32","starting_page":"33568","ending_page":"33586","languages":["eng"],"referee":true,"identifiers":{"doi":["10.18632/oncotarget.5598"],"issn":["1949-2553"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=318276","label":"url"}],"paper_title":{"en":"Susceptibility to bendamustine considerably varies among myeloma cells, but is enhanced in acidic conditions","ja":"Susceptibility to bendamustine considerably varies among myeloma cells, but is enhanced in acidic conditions"},"authors":{"en":[{"name":"Nakamura Shingen"},{"name":"Miki Hirokazu"},{"name":"Oda Asuka"},{"name":"Amachi Ryota"},{"name":"Teramachi Jumpei"},{"name":"Sogabe Kimiko"},{"name":"Fujino Hikaru"},{"name":"Maruhashi Tomoko"},{"name":"Fujii Shiroh"},{"name":"Kagawa Kumiko"},{"name":"Abe Masahiro"}],"ja":[{"name":"中村 信元"},{"name":"三木 浩和"},{"name":"Oda Asuka"},{"name":"Amachi Ryota"},{"name":"寺町 順平"},{"name":"曽我部 公子"},{"name":"Fujino Hikaru"},{"name":"Maruhashi Tomoko"},{"name":"藤井 志朗"},{"name":"賀川 久美子"},{"name":"安倍 正博"}]},"publication_date":"2015-10","publication_name":{"en":"International Journal of Myeloma","ja":"International Journal of Myeloma"},"volume":"Vol.6","number":"No.1","starting_page":"7","ending_page":"11","languages":["eng"],"referee":true,"identifiers":{"issn":["2187-3143"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/109478","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/25739386","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=296654","label":"url"}],"paper_title":{"en":"Double stranded RNA-dependent protein kinase is necessary for TNF--induced osteoclast formation in vitro and in vivo.","ja":"Double stranded RNA-dependent protein kinase is necessary for TNF--induced osteoclast formation in vitro and in vivo."},"authors":{"en":[{"name":"Shinohara Hiroki"},{"name":"Teramachi Jumpei"},{"name":"Okamura Hirohiko"},{"name":"Yang Di"},{"name":"Nagata Toshihiko"},{"name":"Haneji Tatsuji"}],"ja":[{"name":"Shinohara Hiroki"},{"name":"寺町 順平"},{"name":"岡村 裕彦"},{"name":"楊 諦"},{"name":"永田 俊彦"},{"name":"羽地 達次"}]},"description":{"en":"Double-stranded RNA-dependent protein kinase (PKR) is involved in cell cycle progression, cell proliferation, cell differentiation, tumorgenesis, and apoptosis. We previously reported that PKR is required for differentiation and calcification in osteoblasts. TNF- plays a key role in osteoclast differentiation. However, it is unknown about the roles of PKR in the TNF--induced osteoclast differentiation. The expression of PKR in osteoclast precursor RAW264.7 cells increased during TNF--induced osteoclastogenesis. The TNF--induced osteoclast differentiation in bone marrow-derived macrophages and RAW264.7 cells was markedly suppressed by the pre-treatment of PKR inhibitor, 2-aminopurine (2AP), as well as gene silencing of PKR. The expression of gene markers in the differentiated osteoclasts including TRAP, Calcitonin receptor, cathepsin K and ATP6V0d2 was also suppressed by the 2AP treatment. Bone resorption activity of TNF--induced osteoclasts was also supressed by 2AP treatment. Inhibition of PKR supressed the TNF--induced activation of NF-B and MAPK in RAW264.7 cells. 2AP inhibited both the nuclear translocation of NF-B and its transcriptional activity in RAW264.7 cells. 2AP inhibited the TNF--induced expression of NFATc1 and c-fos, master transcription factors in osteoclastogenesis. TNF--induced nuclear translocation of NFATc1 in mature osteoclasts was clearly inhibited by the 2AP treatment. The PKR inhibitor C16 decreased the TNF--induced osteoclast formation and bone resorption in mouse calvaria. The present study indicates that PKR is necessary for the TNF--induced osteoclast differentiation in vitro and in vivo. This article is protected by copyright. All rights reserved.","ja":"Double-stranded RNA-dependent protein kinase (PKR) is involved in cell cycle progression, cell proliferation, cell differentiation, tumorgenesis, and apoptosis. We previously reported that PKR is required for differentiation and calcification in osteoblasts. TNF- plays a key role in osteoclast differentiation. However, it is unknown about the roles of PKR in the TNF--induced osteoclast differentiation. The expression of PKR in osteoclast precursor RAW264.7 cells increased during TNF--induced osteoclastogenesis. The TNF--induced osteoclast differentiation in bone marrow-derived macrophages and RAW264.7 cells was markedly suppressed by the pre-treatment of PKR inhibitor, 2-aminopurine (2AP), as well as gene silencing of PKR. The expression of gene markers in the differentiated osteoclasts including TRAP, Calcitonin receptor, cathepsin K and ATP6V0d2 was also suppressed by the 2AP treatment. Bone resorption activity of TNF--induced osteoclasts was also supressed by 2AP treatment. Inhibition of PKR supressed the TNF--induced activation of NF-B and MAPK in RAW264.7 cells. 2AP inhibited both the nuclear translocation of NF-B and its transcriptional activity in RAW264.7 cells. 2AP inhibited the TNF--induced expression of NFATc1 and c-fos, master transcription factors in osteoclastogenesis. TNF--induced nuclear translocation of NFATc1 in mature osteoclasts was clearly inhibited by the 2AP treatment. The PKR inhibitor C16 decreased the TNF--induced osteoclast formation and bone resorption in mouse calvaria. The present study indicates that PKR is necessary for the TNF--induced osteoclast differentiation in vitro and in vivo. This article is protected by copyright. All rights reserved."},"publication_date":"2015-09","publication_name":{"en":"Journal of Cellular Biochemistry","ja":"Journal of Cellular Biochemistry"},"volume":"Vol.116","number":"No.9","starting_page":"1957","ending_page":"1967","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1002/jcb.25151"],"issn":["1097-4644"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://search.jamas.or.jp/link/ui/2017035595","label":"url"},{"@id":"https://cir.nii.ac.jp/crid/1390292815284471040/","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=303535","label":"url"}],"paper_title":{"en":"Induction of endoplasmic reticulum stress by bortezomib sensitizes myeloma cells to DR5-mediated cell death","ja":"Induction of endoplasmic reticulum stress by bortezomib sensitizes myeloma cells to DR5-mediated cell death"},"authors":{"en":[{"name":"Miki Hirokazu"},{"name":"Nakamura Shingen"},{"name":"Oda A"},{"name":"Amachi R"},{"name":"Watanabe Keiichiro"},{"name":"Hanson D"},{"name":"Teramachi Jumpei"},{"name":"Hiasa Masahiro"},{"name":"Yagi H"},{"name":"Sogabe K"},{"name":"Takahashi M"},{"name":"Maruhashi T"},{"name":"Udaka K"},{"name":"Harada T"},{"name":"Fujii Shiroh"},{"name":"Nakano A"},{"name":"Kagawa Kumiko"},{"name":"Ri M"},{"name":"Iida S"},{"name":"Ozaki Shuji"},{"name":"Matsumoto T"},{"name":"Abe Masahiro"}],"ja":[{"name":"三木 浩和"},{"name":"中村 信元"},{"name":"Oda A"},{"name":"Amachi R"},{"name":"渡邉 佳一郎"},{"name":"Hanson D"},{"name":"寺町 順平"},{"name":"日浅 雅博"},{"name":"Yagi H"},{"name":"Sogabe K"},{"name":"Takahashi M"},{"name":"Maruhashi T"},{"name":"Udaka K"},{"name":"Harada T"},{"name":"藤井 志朗"},{"name":"Nakano A"},{"name":"賀川 久美子"},{"name":"Ri M"},{"name":"Iida S"},{"name":"尾崎 修治"},{"name":"Matsumoto T"},{"name":"安倍 正博"}]},"description":{"en":"TNF-related apoptosis-including ligand/Apo2 (TRAIL)-mediated immunotherapy is an attractive anti-tumor modality with high tumor specificity. In order to improve its therapeutic efficacy, we further need to implement a novel maneuver for sensitization of malignant cells to TRAIL. Bortezomib (BTZ), a novel anti-myeloma (MM) agent, potently induces endoplasmic reticulum (ER) stress to cause apoptosis. Here, we explored the roles of BTZ in the cytotoxicity of anti-TRAIL receptor agonistic antibodies against MM cells with special reference to ER stress. BTZ enhanced the expression of death receptor 5 (DR5) but not DR4 in MM cells at surface protein as well as mRNA levels. However, the DR5 expression was not affected by BTZ without ER stress induction in MM cells with a point mutation in a BTZ-binding proteasome β5 subunit. Tunicamycin, an ER stress inducer, was able to enhance the DR5 expression even in the BTZ-resistant MM cells, suggesting the role of ER stress in up-regulation of DR5 expression. Interestingly, BTZ facilitated extrinsic caspase-mediated apoptosis by anti-DR5 agonistic antibody in MM cells along with reducing c-FLICE-like interleukin protein, a caspase 8 inhibitor. These results suggest that BTZ enhances DR5 expression and its downstream apoptotic signaling through ER stress to sensitize MM cells to TRAIL-mediated immunotherapy.
","ja":"TNF-related apoptosis-including ligand/Apo2 (TRAIL)-mediated immunotherapy is an attractive anti-tumor modality with high tumor specificity. In order to improve its therapeutic efficacy, we further need to implement a novel maneuver for sensitization of malignant cells to TRAIL. Bortezomib (BTZ), a novel anti-myeloma (MM) agent, potently induces endoplasmic reticulum (ER) stress to cause apoptosis. Here, we explored the roles of BTZ in the cytotoxicity of anti-TRAIL receptor agonistic antibodies against MM cells with special reference to ER stress. BTZ enhanced the expression of death receptor 5 (DR5) but not DR4 in MM cells at surface protein as well as mRNA levels. However, the DR5 expression was not affected by BTZ without ER stress induction in MM cells with a point mutation in a BTZ-binding proteasome β5 subunit. Tunicamycin, an ER stress inducer, was able to enhance the DR5 expression even in the BTZ-resistant MM cells, suggesting the role of ER stress in up-regulation of DR5 expression. Interestingly, BTZ facilitated extrinsic caspase-mediated apoptosis by anti-DR5 agonistic antibody in MM cells along with reducing c-FLICE-like interleukin protein, a caspase 8 inhibitor. These results suggest that BTZ enhances DR5 expression and its downstream apoptotic signaling through ER stress to sensitize MM cells to TRAIL-mediated immunotherapy.
"},"publication_date":"2015-01","publication_name":{"en":"International Journal of Myeloma","ja":"International Journal of Myeloma"},"volume":"Vol.5","number":"No.1","starting_page":"1","ending_page":"7","languages":["eng"],"referee":true,"identifiers":{"doi":["10.57352/ijm.5.1_1"],"issn":["2187-3143"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/24949891","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84905178655&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=287884","label":"url"}],"paper_title":{"en":"Reduction of PP2A C stimulates adipogenesis by regulating the Wnt/GSK-3/-catenin pathway and PPAR expression","ja":"Reduction of PP2A C stimulates adipogenesis by regulating the Wnt/GSK-3/-catenin pathway and PPAR expression"},"authors":{"en":[{"name":"Okamura Hirohiko"},{"name":"Yang Di"},{"name":"Yoshida Kaya"},{"name":"Teramachi Jumpei"},{"name":"Haneji Tatsuji"}],"ja":[{"name":"岡村 裕彦"},{"name":"楊 諦"},{"name":"吉田 賀弥"},{"name":"寺町 順平"},{"name":"羽地 達次"}]},"description":{"en":"Serine/threonine protein phosphatase 2A (PP2A) regulates several physiological processes such as the cell cycle, cell growth, apoptosis, and signal transduction. In this study, we examined the expression and role of PP2A Cα in adipocyte differentiation. PP2A Cα expression and PP2A activity decreased during adipocyte differentiation in C3H10T1/2 and 3T3-L1 cells and the expression of adipocyte marker genes such as PPARγ and adiponectin increased. To further clarify the role of PP2A Cα in adipocyte differentiation, we constructed PP2A knockdown cells by infecting C3H10T1/2 cells with a lentivirus expressing a shRNA specific for the PP2A Cα (shPP2A cells). Silencing of PP2A Cα in C3H10T1/2 cells dramatically stimulated adipocyte differentiation and lipid accumulation, which were accompanied by expression of adipocyte marker genes. Silencing of PP2A Cα suppressed Wnt10b expression and reduced the levels of the inactivated form of GSK-3β (phospho-GSK-3β), leading to the reduction of β-catenin levels in the nucleus and its transcriptional activity. Treatment with LiCl, a GSK-3β inhibitor, and inhibition of PPARγ expression suppressed the accelerated adipogenesis of shPP2A cells. Our data indicate that PP2A Cα plays an important role in the regulation of adipocyte differentiation by regulating the Wnt/GSK-3β/β-catenin pathway and PPARγ expression.","ja":"Serine/threonine protein phosphatase 2A (PP2A) regulates several physiological processes such as the cell cycle, cell growth, apoptosis, and signal transduction. In this study, we examined the expression and role of PP2A Cα in adipocyte differentiation. PP2A Cα expression and PP2A activity decreased during adipocyte differentiation in C3H10T1/2 and 3T3-L1 cells and the expression of adipocyte marker genes such as PPARγ and adiponectin increased. To further clarify the role of PP2A Cα in adipocyte differentiation, we constructed PP2A knockdown cells by infecting C3H10T1/2 cells with a lentivirus expressing a shRNA specific for the PP2A Cα (shPP2A cells). Silencing of PP2A Cα in C3H10T1/2 cells dramatically stimulated adipocyte differentiation and lipid accumulation, which were accompanied by expression of adipocyte marker genes. Silencing of PP2A Cα suppressed Wnt10b expression and reduced the levels of the inactivated form of GSK-3β (phospho-GSK-3β), leading to the reduction of β-catenin levels in the nucleus and its transcriptional activity. Treatment with LiCl, a GSK-3β inhibitor, and inhibition of PPARγ expression suppressed the accelerated adipogenesis of shPP2A cells. Our data indicate that PP2A Cα plays an important role in the regulation of adipocyte differentiation by regulating the Wnt/GSK-3β/β-catenin pathway and PPARγ expression."},"publication_date":"2014-06-17","publication_name":{"en":"Biochimica et Biophysica Acta (BBA) - Molecular Cell Research","ja":"Biochimica et Biophysica Acta (BBA) - Molecular Cell Research"},"volume":"Vol.1843","number":"No.11","starting_page":"2376","ending_page":"2384","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.bbamcr.2014.06.008"],"issn":["0167-4889"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/24339057","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84901272730&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=279540","label":"url"}],"paper_title":{"en":"Increased IL-6 expression in osteoclasts is necessary but not sufficient for the development of Paget's disease of bone.","ja":"Increased IL-6 expression in osteoclasts is necessary but not sufficient for the development of Paget's disease of bone."},"authors":{"en":[{"name":"Teramachi Jumpei"},{"name":"Zhou Hua"},{"name":"Subler Mark A"},{"name":"Kitagawa Yukiko"},{"name":"Galson Deborah L"},{"name":"Dempster David W"},{"name":"Windle Jolene J"},{"name":"Kurihara Noriyoshi"},{"name":"Roodman G David"}],"ja":[{"name":"寺町 順平"},{"name":"Zhou Hua"},{"name":"Subler Mark A"},{"name":"Kitagawa Yukiko"},{"name":"Galson Deborah L"},{"name":"Dempster David W"},{"name":"Windle Jolene J"},{"name":"Kurihara Noriyoshi"},{"name":"Roodman G David"}]},"description":{"en":"Measles virus nucleocapsid protein (MVNP) expression in osteoclasts (OCLs) and mutation of the SQSTM1 (p62) gene contribute to the increased OCL activity in Paget's disease (PD). OCLs expressing MVNP display many of the features of PD OCLs. Interleukin-6 (IL-6) production is essential for the pagetic phenotype, because transgenic mice with MVNP targeted to OCLs develop pagetic OCLs and lesions, but this phenotype is absent when MVNP mice are bred to IL-6(-/-) mice. In contrast, mutant p62 expression in OCL precursors promotes receptor activator of NF-κB ligand (RANKL) hyperresponsivity and increased OCL production, but OCLs that form have normal morphology, are not hyperresponsive to 1,25-dihydroxyvitamin D3 (1,25-(OH)2 D3 ), nor produce elevated levels of IL-6. We previously generated p62(P394L) knock-in mice (p62KI) and found that although OCL numbers were increased, the mice did not develop pagetic lesions. However, mice expressing both MVNP and p62KI developed more exuberant pagetic lesions than mice expressing MVNP alone. To examine the role of elevated IL-6 in PD and determine if MVNP mediates its effects primarily through elevation of IL-6, we generated transgenic mice that overexpress IL-6 driven by the tartrate-resistant acid phosphatase (TRAP) promoter (TIL-6 mice) and produce IL-6 at levels comparable to MVNP mice. These were crossed with p62KI mice to determine whether IL-6 overexpression cooperates with mutant p62 to produce pagetic lesions. OCL precursors from p62KI/TIL-6 mice formed greater numbers of OCLs than either p62KI or TIL-6 OCL precursors in response to 1,25-(OH)2 D3 . Histomorphometric analysis of bones from p62KI/TIL-6 mice revealed increased OCL numbers per bone surface area compared to wild-type (WT) mice. However, micro-quantitative CT (µQCT) analysis did not reveal significant differences between p62KI/TIL-6 and WT mice, and no pagetic OCLs or lesions were detected in vivo. Thus, increased IL-6 expression in OCLs from p62KI mice contributes to increased responsivity to 1,25-(OH)2 D3 and increased OCL numbers, but is not sufficient to induce Paget's-like OCLs or bone lesions in vivo.","ja":"Measles virus nucleocapsid protein (MVNP) expression in osteoclasts (OCLs) and mutation of the SQSTM1 (p62) gene contribute to the increased OCL activity in Paget's disease (PD). OCLs expressing MVNP display many of the features of PD OCLs. Interleukin-6 (IL-6) production is essential for the pagetic phenotype, because transgenic mice with MVNP targeted to OCLs develop pagetic OCLs and lesions, but this phenotype is absent when MVNP mice are bred to IL-6(-/-) mice. In contrast, mutant p62 expression in OCL precursors promotes receptor activator of NF-κB ligand (RANKL) hyperresponsivity and increased OCL production, but OCLs that form have normal morphology, are not hyperresponsive to 1,25-dihydroxyvitamin D3 (1,25-(OH)2 D3 ), nor produce elevated levels of IL-6. We previously generated p62(P394L) knock-in mice (p62KI) and found that although OCL numbers were increased, the mice did not develop pagetic lesions. However, mice expressing both MVNP and p62KI developed more exuberant pagetic lesions than mice expressing MVNP alone. To examine the role of elevated IL-6 in PD and determine if MVNP mediates its effects primarily through elevation of IL-6, we generated transgenic mice that overexpress IL-6 driven by the tartrate-resistant acid phosphatase (TRAP) promoter (TIL-6 mice) and produce IL-6 at levels comparable to MVNP mice. These were crossed with p62KI mice to determine whether IL-6 overexpression cooperates with mutant p62 to produce pagetic lesions. OCL precursors from p62KI/TIL-6 mice formed greater numbers of OCLs than either p62KI or TIL-6 OCL precursors in response to 1,25-(OH)2 D3 . Histomorphometric analysis of bones from p62KI/TIL-6 mice revealed increased OCL numbers per bone surface area compared to wild-type (WT) mice. However, micro-quantitative CT (µQCT) analysis did not reveal significant differences between p62KI/TIL-6 and WT mice, and no pagetic OCLs or lesions were detected in vivo. Thus, increased IL-6 expression in OCLs from p62KI mice contributes to increased responsivity to 1,25-(OH)2 D3 and increased OCL numbers, but is not sufficient to induce Paget's-like OCLs or bone lesions in vivo."},"publication_date":"2014-06","publication_name":{"en":"Journal of Bone and Mineral Research","ja":"Journal of Bone and Mineral Research"},"volume":"Vol.29","number":"No.6","starting_page":"1456","ending_page":"1465","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1002/jbmr.2158"],"issn":["1523-4681"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/24787487","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=283755","label":"url"}],"paper_title":{"en":"Pim-2 kinase is an important target of treatment for tumor progression and bone loss in myeloma.","ja":"Pim-2 kinase is an important target of treatment for tumor progression and bone loss in myeloma."},"authors":{"en":[{"name":"Hiasa Masahiro"},{"name":"Teramachi Jumpei"},{"name":"Oda A"},{"name":"Amachi Ryota"},{"name":"Harada T"},{"name":"Nakamura Shingen"},{"name":"Miki Hirokazu"},{"name":"Fujii Shiroh"},{"name":"Kagawa Kumiko"},{"name":"Watanabe Keiichiro"},{"name":"Endo Itsuro"},{"name":"Kuroda Y"},{"name":"Yoneda T"},{"name":"Tsuji Daisuke"},{"name":"Nakao Michiyasu"},{"name":"Tanaka Eiji"},{"name":"Hamada Kenichi"},{"name":"Sano Shigeki"},{"name":"Itou Kouji"},{"name":"Matsumoto Toshio"},{"name":"Abe Masahiro"}],"ja":[{"name":"日浅 雅博"},{"name":"寺町 順平"},{"name":"Oda A"},{"name":"天知 良太"},{"name":"Harada T"},{"name":"中村 信元"},{"name":"三木 浩和"},{"name":"藤井 志朗"},{"name":"賀川 久美子"},{"name":"渡邉 佳一郎"},{"name":"遠藤 逸朗"},{"name":"Kuroda Y"},{"name":"Yoneda T"},{"name":"辻 大輔"},{"name":"中尾 允泰"},{"name":"田中 栄二"},{"name":"浜田 賢一"},{"name":"佐野 茂樹"},{"name":"伊藤 孝司"},{"name":"松本 俊夫"},{"name":"安倍 正博"}]},"description":{"en":"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.","ja":"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."},"publication_date":"2014-05-02","publication_name":{"en":"Leukemia","ja":"Leukemia"},"languages":["eng"],"referee":true,"identifiers":{"doi":["10.1038/leu.2014.147"],"issn":["1476-5551"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/24603641","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84898968069&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=287284","label":"url"}],"paper_title":{"en":"Calcium hydroxide suppresses the virulence of lipopolysaccharide from Porphyromonas endodontalis to bone cells","ja":"Calcium hydroxide suppresses the virulence of lipopolysaccharide from Porphyromonas endodontalis to bone cells"},"authors":{"en":[{"name":"Guo J"},{"name":"Yang Di"},{"name":"Okamura Hirohiko"},{"name":"Teramachi Jumpei"},{"name":"Ochiai Kazuhiko"},{"name":"Qiu L"},{"name":"Haneji Tatsuji"}],"ja":[{"name":"Guo J"},{"name":"楊 諦"},{"name":"岡村 裕彦"},{"name":"寺町 順平"},{"name":"落合 和彦"},{"name":"Qiu L"},{"name":"羽地 達次"}]},"description":{"en":"Porphyromonas endodontalis and its main virulence factor, lipopolysaccharide (LPS), are associated with the development of periapical diseases and alveolar bone loss. Calcium hydroxide is commonly used for endodontic therapy. However, the effects of calcium hydroxide on the virulence of P. endodontalis LPS and the mechanism of P. endodontalis LPS-induced bone destruction are not clear. Calcium hydroxide rescued the P. endodontalis LPS-suppressed viability of MC3T3-E1 cells and activity of nuclear factor-κB (NF-κB) in these cells, resulting in the reduced expression of interleukin-6 and tumor necrosis factor-α. In addition, calcium hydroxide inhibited P. endodontalis LPS-induced osteoclastogenesis by decreasing the activities of NF-κB, p38, and ERK1/2 and the expression of nuclear factor of activated T-cell cytoplasmic 1 in RAW264.7 cells. Calcium hydroxide also rescued the P. endodontalis LPS-induced osteoclastogenesis and bone destruction in mouse calvaria. Taken together, our present results indicate that calcium hydroxide suppressed bone destruction by attenuating the virulence of P. endodontalis LPS on bone cells.","ja":"Porphyromonas endodontalis and its main virulence factor, lipopolysaccharide (LPS), are associated with the development of periapical diseases and alveolar bone loss. Calcium hydroxide is commonly used for endodontic therapy. However, the effects of calcium hydroxide on the virulence of P. endodontalis LPS and the mechanism of P. endodontalis LPS-induced bone destruction are not clear. Calcium hydroxide rescued the P. endodontalis LPS-suppressed viability of MC3T3-E1 cells and activity of nuclear factor-κB (NF-κB) in these cells, resulting in the reduced expression of interleukin-6 and tumor necrosis factor-α. In addition, calcium hydroxide inhibited P. endodontalis LPS-induced osteoclastogenesis by decreasing the activities of NF-κB, p38, and ERK1/2 and the expression of nuclear factor of activated T-cell cytoplasmic 1 in RAW264.7 cells. Calcium hydroxide also rescued the P. endodontalis LPS-induced osteoclastogenesis and bone destruction in mouse calvaria. Taken together, our present results indicate that calcium hydroxide suppressed bone destruction by attenuating the virulence of P. endodontalis LPS on bone cells."},"publication_date":"2014-03-06","publication_name":{"en":"Journal of Dental Research","ja":"Journal of Dental Research"},"volume":"Vol.93","number":"No.5","starting_page":"508","ending_page":"513","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1177/0022034514526886"],"issn":["1544-0591"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/23591640","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84876527228&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=269189","label":"url"}],"paper_title":{"en":"Okadaic acid activates the PKR pathway and induces apoptosis through PKR stimulation in MG63 osteoblast-like cells.","ja":"Okadaic acid activates the PKR pathway and induces apoptosis through PKR stimulation in MG63 osteoblast-like cells."},"authors":{"en":[{"name":"Haneji Tatsuji"},{"name":"Hirashima Kanji"},{"name":"Teramachi Jumpei"},{"name":"Morimoto Hiroyuki"}],"ja":[{"name":"羽地 達次"},{"name":"Hirashima Kanji"},{"name":"寺町 順平"},{"name":"Morimoto Hiroyuki"}]},"description":{"en":"Double-stranded RNA-dependent protein kinase (PKR) is one of the players in the cellular antiviral responses and is involved in transcriptional stimulation through activation of NF-κB. Treatment of the human osteosarcoma cell line MG63 with the protein phosphatase inhibitor okadaic acid stimulated the expression and phosphorylation of IκBα, as judged from the results of real-time PCR and western blot analysis. We investigated the functional relationship between PKR and signal transduction of NF-κB by establishing PKR-K/R cells that produced a catalytically inactive mutant of PKR. Phosphorylation of eIF-2α, a substrate of PKR, was not stimulated by okadaic acid in the PKR-K/R cells, whereas okadaic acid induced phosphorylation of eIF-2α in MG63 cells. Phosphorylation of NF-κB in MG63 cells was stimulated by okadaic acid; however, okadaic acid did not induce phosphorylation of NF-κB in the PKR-K/R cells. Finally, okadaic acid-induced apoptosis was inhibited in the PKR-K/R cells. Our results suggest that okadaic acid-induced phosphorylation of IκBα was mediated by PKR kinase activity, thus, indicating the involvement of this kinase in the control mechanism governing the activation of NF-κB and induction of apoptosis.","ja":"Double-stranded RNA-dependent protein kinase (PKR) is one of the players in the cellular antiviral responses and is involved in transcriptional stimulation through activation of NF-κB. Treatment of the human osteosarcoma cell line MG63 with the protein phosphatase inhibitor okadaic acid stimulated the expression and phosphorylation of IκBα, as judged from the results of real-time PCR and western blot analysis. We investigated the functional relationship between PKR and signal transduction of NF-κB by establishing PKR-K/R cells that produced a catalytically inactive mutant of PKR. Phosphorylation of eIF-2α, a substrate of PKR, was not stimulated by okadaic acid in the PKR-K/R cells, whereas okadaic acid induced phosphorylation of eIF-2α in MG63 cells. Phosphorylation of NF-κB in MG63 cells was stimulated by okadaic acid; however, okadaic acid did not induce phosphorylation of NF-κB in the PKR-K/R cells. Finally, okadaic acid-induced apoptosis was inhibited in the PKR-K/R cells. Our results suggest that okadaic acid-induced phosphorylation of IκBα was mediated by PKR kinase activity, thus, indicating the involvement of this kinase in the control mechanism governing the activation of NF-κB and induction of apoptosis."},"publication_date":"2013-06","publication_name":{"en":"International Journal of Oncology","ja":"International Journal of Oncology"},"volume":"Vol.42","number":"No.6","starting_page":"1904","ending_page":"1910","languages":["eng"],"referee":true,"identifiers":{"doi":["10.3892/ijo.2013.1911"],"issn":["1791-2423"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/23426901","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=263750","label":"url"}],"paper_title":{"en":"Role of ATF7-TAF12 interactions in the vitamin D response hypersensitivity of osteoclast precursors in Paget's disease","ja":"Role of ATF7-TAF12 interactions in the vitamin D response hypersensitivity of osteoclast precursors in Paget's disease"},"authors":{"en":[{"name":"Teramachi Jumpei"},{"name":"Hiruma Yuko"},{"name":"Ishizuka Seiichi"},{"name":"Ishizuka Hisako"},{"name":"Brown P Jacques"},{"name":"Michou Laëtitia"},{"name":"Cao Huiling"},{"name":"Galson L Deborah"},{"name":"Subler A Mark"},{"name":"Zhou Hua"},{"name":"Dempster David W"},{"name":"Windle J Jolene"},{"name":"Roodman David G."},{"name":"Kurihara Noriyoshi"}],"ja":[{"name":"寺町 順平"},{"name":"Hiruma Yuko"},{"name":"Ishizuka Seiichi"},{"name":"Ishizuka Hisako"},{"name":"Brown P Jacques"},{"name":"Michou Laëtitia"},{"name":"Cao Huiling"},{"name":"Galson L Deborah"},{"name":"Subler A Mark"},{"name":"Zhou Hua"},{"name":"Dempster David W"},{"name":"Windle J Jolene"},{"name":"Roodman David G."},{"name":"Kurihara Noriyoshi"}]},"description":{"en":"Osteoclast (OCL) precursors from many Paget's disease (PD) patients express measles virus nucleocapsid protein (MVNP) and are hypersensitive to 1,25-dihydroxyvitamin D2 (1,25-(OH)2D3; also know as calcitriol). The increased 1,25-(OH)2D3 sensitivity is mediated by transcription initiation factor TFIID subunit 12 (TAF12), a coactivator of the vitamin D receptor (VDR), which is present at much higher levels in MVNP-expressing OCL precursors than normals. These results suggest that TAF12 plays an important role in the abnormal OCL activity in PD. However, the molecular mechanisms underlying both 1,25-(OH)2D3's effects on OCL formation and the contribution of TAF12 to these effects in both normals and PD patients are unclear. Inhibition of TAF12 with a specific TAF12 antisense construct decreased OCL formation and OCL precursors' sensitivity to 1,25-(OH)2D3 in PD patient bone marrow samples. Further, OCL precursors from transgenic mice in which TAF12 expression was targeted to the OCL lineage (tartrate-resistant acid phosphatase [TRAP]-TAF12 mice), formed OCLs at very low levels of 1,25-(OH)2D3, although the OCLs failed to exhibit other hallmarks of PD OCLs, including receptor activator of NF-κB ligand (RANKL) hypersensitivity and hypermultinucleation. Chromatin immunoprecipitation (ChIP) analysis of OCL precursors using an anti-TAF12 antibody demonstrated that TAF12 binds the 24-hydroxylase (CYP24A1) promoter, which contains two functional vitamin D response elements (VDREs), in the presence of 1,25-(OH)2D3. Because TAF12 directly interacts with the cyclic adenosine monophosphate-dependent activating transcription factor 7 (ATF7) and potentiates ATF7-induced transcriptional activation of ATF7-driven genes in other cell types, we determined whether TAF12 is a functional partner of ATF7 in OCL precursors. Immunoprecipitation of lysates from either wild-type (WT) or MVNP-expressing OCL with an anti-TAF12 antibody, followed by blotting with an anti-ATF7 antibody, or vice versa, showed that TAF12 and ATF7 physically interact in OCLs. Knockdown of ATF7 in MVNP-expressing cells decreased cytochrome P450, family 24, subfamily A, polypeptide 1 (CYP24A1) induction by1,25-(OH)2D3, as well as TAF12 binding to the CYP24A1 promoter. These results show that ATF7 interacts with TAF12 and contributes to the hypersensitivity of OCL precursors to 1,25-(OH)2D3 in PD.","ja":"Osteoclast (OCL) precursors from many Paget's disease (PD) patients express measles virus nucleocapsid protein (MVNP) and are hypersensitive to 1,25-dihydroxyvitamin D2 (1,25-(OH)2D3; also know as calcitriol). The increased 1,25-(OH)2D3 sensitivity is mediated by transcription initiation factor TFIID subunit 12 (TAF12), a coactivator of the vitamin D receptor (VDR), which is present at much higher levels in MVNP-expressing OCL precursors than normals. These results suggest that TAF12 plays an important role in the abnormal OCL activity in PD. However, the molecular mechanisms underlying both 1,25-(OH)2D3's effects on OCL formation and the contribution of TAF12 to these effects in both normals and PD patients are unclear. Inhibition of TAF12 with a specific TAF12 antisense construct decreased OCL formation and OCL precursors' sensitivity to 1,25-(OH)2D3 in PD patient bone marrow samples. Further, OCL precursors from transgenic mice in which TAF12 expression was targeted to the OCL lineage (tartrate-resistant acid phosphatase [TRAP]-TAF12 mice), formed OCLs at very low levels of 1,25-(OH)2D3, although the OCLs failed to exhibit other hallmarks of PD OCLs, including receptor activator of NF-κB ligand (RANKL) hypersensitivity and hypermultinucleation. Chromatin immunoprecipitation (ChIP) analysis of OCL precursors using an anti-TAF12 antibody demonstrated that TAF12 binds the 24-hydroxylase (CYP24A1) promoter, which contains two functional vitamin D response elements (VDREs), in the presence of 1,25-(OH)2D3. Because TAF12 directly interacts with the cyclic adenosine monophosphate-dependent activating transcription factor 7 (ATF7) and potentiates ATF7-induced transcriptional activation of ATF7-driven genes in other cell types, we determined whether TAF12 is a functional partner of ATF7 in OCL precursors. Immunoprecipitation of lysates from either wild-type (WT) or MVNP-expressing OCL with an anti-TAF12 antibody, followed by blotting with an anti-ATF7 antibody, or vice versa, showed that TAF12 and ATF7 physically interact in OCLs. Knockdown of ATF7 in MVNP-expressing cells decreased cytochrome P450, family 24, subfamily A, polypeptide 1 (CYP24A1) induction by1,25-(OH)2D3, as well as TAF12 binding to the CYP24A1 promoter. These results show that ATF7 interacts with TAF12 and contributes to the hypersensitivity of OCL precursors to 1,25-(OH)2D3 in PD."},"publication_date":"2013-06","publication_name":{"en":"Journal of Bone and Mineral Research","ja":"Journal of Bone and Mineral Research"},"volume":"Vol.28","number":"No.6","starting_page":"1489","ending_page":"1500","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1002/jbmr.1884"],"issn":["1523-4681"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/23111587","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=263751","label":"url"}],"paper_title":{"en":"Adenosine blocks aminopterin-induced suppression of osteoclast differentiation","ja":"Adenosine blocks aminopterin-induced suppression of osteoclast differentiation"},"authors":{"en":[{"name":"Teramachi Jumpei"},{"name":"Kukita Akiko"},{"name":"Qu Pengfei"},{"name":"Wada Naohisa"},{"name":"Li Yin-Ji"},{"name":"Nakamura Seiji"},{"name":"Kukita Toshio"}],"ja":[{"name":"寺町 順平"},{"name":"Kukita Akiko"},{"name":"Qu Pengfei"},{"name":"Wada Naohisa"},{"name":"Li Yin-Ji"},{"name":"Nakamura Seiji"},{"name":"Kukita Toshio"}]},"description":{"en":"To search cell surface molecules involved in the regulation of osteoclastogenesis, especially in fusion process, it is one powerful approach to obtain monoclonal antibodies bearing ability to block formation of multinucleated osteoclasts. Ideally, direct bio-assay of hybridoma supernatants is quite convenient to screen monoclonal antibodies of interest from numerous culture wells. However, addition of hybridoma supernatant containing hypoxanthine-aminopterin-thymidine (HAT), components of the selection medium, to whole bone marrow cultures strikingly suppressed osteoclastogenesis. Here we clarified aminopterin is the responsible component in HAT medium to inhibit osteoclastogenesis. Methotrexate (MTX), mono-methylated aminopterin, showed similar suppressive effect on osteoclastogenesis. When bone marrow cells were cultured in the presence of all nucleosides, aminopterin and MTX-induced suppression of osteoclastogenesis was abrogated. Among four nucleosides only adenosine canceled aminopterin-induced suppression of osteoclastogenesis. Direct bio-assay of hybridoma supernatant containing HAT selection medium is now available to screen monoclonal antibodies if adenosine-containing culture medium was utilized for evaluating osteoclastogenesis.","ja":"To search cell surface molecules involved in the regulation of osteoclastogenesis, especially in fusion process, it is one powerful approach to obtain monoclonal antibodies bearing ability to block formation of multinucleated osteoclasts. Ideally, direct bio-assay of hybridoma supernatants is quite convenient to screen monoclonal antibodies of interest from numerous culture wells. However, addition of hybridoma supernatant containing hypoxanthine-aminopterin-thymidine (HAT), components of the selection medium, to whole bone marrow cultures strikingly suppressed osteoclastogenesis. Here we clarified aminopterin is the responsible component in HAT medium to inhibit osteoclastogenesis. Methotrexate (MTX), mono-methylated aminopterin, showed similar suppressive effect on osteoclastogenesis. When bone marrow cells were cultured in the presence of all nucleosides, aminopterin and MTX-induced suppression of osteoclastogenesis was abrogated. Among four nucleosides only adenosine canceled aminopterin-induced suppression of osteoclastogenesis. Direct bio-assay of hybridoma supernatant containing HAT selection medium is now available to screen monoclonal antibodies if adenosine-containing culture medium was utilized for evaluating osteoclastogenesis."},"publication_date":"2013-01","publication_name":{"en":"Journal of Bone and Mineral Metabolism","ja":"Journal of Bone and Mineral Metabolism"},"volume":"Vol.31","starting_page":"64","ending_page":"70","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1007/s00774-012-0388-7"],"issn":["1435-5604"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/23072339","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=263753","label":"url"}],"paper_title":{"en":"Lead Discovery, Chemistry Optimization, and Biological Evaluation Studies of Novel Biamide Derivatives as CB2 Receptor Inverse Agonists and Osteoclast Inhibitors","ja":"Lead Discovery, Chemistry Optimization, and Biological Evaluation Studies of Novel Biamide Derivatives as CB2 Receptor Inverse Agonists and Osteoclast Inhibitors"},"authors":{"en":[{"name":"Yang Peng"},{"name":"Myint Kyaw-Zeyar"},{"name":"Tong Qin"},{"name":"Feng Rentian"},{"name":"Cao Haiping"},{"name":"Almehizia Abdulrahman A."},{"name":"Alqarni Mohammed Hamed"},{"name":"Wang Lirong"},{"name":"Bartlow Patrick"},{"name":"Gao Yingdai"},{"name":"Gertsch Jürg"},{"name":"Teramachi Jumpei"},{"name":"Kurihara Noriyoshi"},{"name":"Roodman David G."},{"name":"Cheng Tao"},{"name":"Xie Xiang-Qun"}],"ja":[{"name":"Yang Peng"},{"name":"Myint Kyaw-Zeyar"},{"name":"Tong Qin"},{"name":"Feng Rentian"},{"name":"Cao Haiping"},{"name":"Almehizia Abdulrahman A."},{"name":"Alqarni Mohammed Hamed"},{"name":"Wang Lirong"},{"name":"Bartlow Patrick"},{"name":"Gao Yingdai"},{"name":"Gertsch Jürg"},{"name":"寺町 順平"},{"name":"Kurihara Noriyoshi"},{"name":"Roodman David G."},{"name":"Cheng Tao"},{"name":"Xie Xiang-Qun"}]},"description":{"en":"N,N'-((4-(Dimethylamino)phenyl)methylene)bis(2-phenylacetamide) was discovered by using 3D pharmacophore database searches and was biologically confirmed as a new class of CB(2) inverse agonists. Subsequently, 52 derivatives were designed and synthesized through lead chemistry optimization by modifying the rings A-C and the core structure in further SAR studies. Five compounds were developed and also confirmed as CB(2) inverse agonists with the highest CB(2) binding affinity (CB(2)K(i) of 22-85 nM, EC(50) of 4-28 nM) and best selectivity (CB(1)/CB(2) of 235- to 909-fold). Furthermore, osteoclastogenesis bioassay indicated that PAM compounds showed great inhibition of osteoclast formation. Especially, compound 26 showed 72% inhibition activity even at the low concentration of 0.1 μM. The cytotoxicity assay suggested that the inhibition of PAM compounds on osteoclastogenesis did not result from its cytotoxicity. Therefore, these PAM derivatives could be used as potential leads for the development of a new type of antiosteoporosis agent.","ja":"N,N'-((4-(Dimethylamino)phenyl)methylene)bis(2-phenylacetamide) was discovered by using 3D pharmacophore database searches and was biologically confirmed as a new class of CB(2) inverse agonists. Subsequently, 52 derivatives were designed and synthesized through lead chemistry optimization by modifying the rings A-C and the core structure in further SAR studies. Five compounds were developed and also confirmed as CB(2) inverse agonists with the highest CB(2) binding affinity (CB(2)K(i) of 22-85 nM, EC(50) of 4-28 nM) and best selectivity (CB(1)/CB(2) of 235- to 909-fold). Furthermore, osteoclastogenesis bioassay indicated that PAM compounds showed great inhibition of osteoclast formation. Especially, compound 26 showed 72% inhibition activity even at the low concentration of 0.1 μM. The cytotoxicity assay suggested that the inhibition of PAM compounds on osteoclastogenesis did not result from its cytotoxicity. Therefore, these PAM derivatives could be used as potential leads for the development of a new type of antiosteoporosis agent."},"publication_date":"2012-10","publication_name":{"en":"Journal of Medicinal Chemistry","ja":"Journal of Medicinal Chemistry"},"volume":"Vol.55","number":"No.22","starting_page":"9973","ending_page":"9987","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1021/jm301212u"],"issn":["1520-4804"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"http://ci.nii.ac.jp/naid/130001258485/","label":"url"},{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/114979","label":"url"},{"@id":"https://cir.nii.ac.jp/crid/1390282679837485056/","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=251594","label":"url"}],"paper_title":{"en":"Interaction of protein phosphatase 1δ with nucleophosmin in human osteoblastic cells","ja":"Interaction of protein phosphatase 1δ with nucleophosmin in human osteoblastic cells"},"authors":{"en":[{"name":"Haneji Tatsuji"},{"name":"Teramachi Jumpei"},{"name":"Hirashima Kanji"},{"name":"Kimura Koji"},{"name":"Morimoto Hiroyuki"}],"ja":[{"name":"羽地 達次"},{"name":"寺町 順平"},{"name":"Hirashima Kanji"},{"name":"Kimura Koji"},{"name":"森本 景之"}]},"description":{"en":"Protein phosphorylation and dephosphorylation has been recognized as an essential mechanism in the regulation of cellular metabolism and function in various tissues. Serine and threonine protein phosphatases (PP) are divided into four categories: PP1, PP2A, PP2B, and PP2C. At least four isoforms of PP1 catalytic subunit in rat, PP1α, PP1γ1, PP1γ2, and PP1δ, were isolated. In the present study, we examined the localization and expression of PP1δ in human osteoblastic Saos-2 cells. Anti-PP1δ antibody recognized a protein present in the nucleolar regions in Saos-2 cells. Cellular fractionation revealed that PP1δ is a 37 kDa protein localized in the nucleolus. Nucleophosmin is a nucleolar phosphoprotein and located mainly in the nucleolus. Staining pattern of nucleophosmin in Saos-2 cells was similar to that of PP1δ. PP1δ and nucleophosmin were specifically stained as dots in the nucleus. Dual fluorescence images revealed that PP1δ and nucleophosmin were localized in the same regions in the nucleolus. Similar distribution patterns of PP1δ and nucleophosmin were observed in osteoblastic MG63 cells. The interaction of PP1δ and nucleophosmin was also shown by immunoprecipitation and Western analysis. These results indicated that PP1δ associate with nucleophosmin directly in the nucleolus and suggested that nucleophosmin is one of the candidate substrate for PP1δ.","ja":"Protein phosphorylation and dephosphorylation has been recognized as an essential mechanism in the regulation of cellular metabolism and function in various tissues. Serine and threonine protein phosphatases (PP) are divided into four categories: PP1, PP2A, PP2B, and PP2C. At least four isoforms of PP1 catalytic subunit in rat, PP1α, PP1γ1, PP1γ2, and PP1δ, were isolated. In the present study, we examined the localization and expression of PP1δ in human osteoblastic Saos-2 cells. Anti-PP1δ antibody recognized a protein present in the nucleolar regions in Saos-2 cells. Cellular fractionation revealed that PP1δ is a 37 kDa protein localized in the nucleolus. Nucleophosmin is a nucleolar phosphoprotein and located mainly in the nucleolus. Staining pattern of nucleophosmin in Saos-2 cells was similar to that of PP1δ. PP1δ and nucleophosmin were specifically stained as dots in the nucleus. Dual fluorescence images revealed that PP1δ and nucleophosmin were localized in the same regions in the nucleolus. Similar distribution patterns of PP1δ and nucleophosmin were observed in osteoblastic MG63 cells. The interaction of PP1δ and nucleophosmin was also shown by immunoprecipitation and Western analysis. These results indicated that PP1δ associate with nucleophosmin directly in the nucleolus and suggested that nucleophosmin is one of the candidate substrate for PP1δ."},"publication_date":"2012","publication_name":{"en":"Acta Histochemica et Cytochemica","ja":"Acta Histochemica et Cytochemica"},"volume":"Vol.45","number":"No.1","starting_page":"1","ending_page":"7","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1267/ahc.11041"],"issn":["0044-5991"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/21590684","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=263755","label":"url"}],"paper_title":{"en":"The transcription factor FBI-1/OCZF/LRF is expressed in osteoclasts and regulates RANKL-induced osteoclast formation in vitro and in vivo","ja":"The transcription factor FBI-1/OCZF/LRF is expressed in osteoclasts and regulates RANKL-induced osteoclast formation in vitro and in vivo"},"authors":{"en":[{"name":"Kukita Akiko"},{"name":"Kukita Toshio"},{"name":"Nagata Kengo"},{"name":"Teramachi Jumpei"},{"name":"Li Yin-Ji"},{"name":"Yoshida Hiroki"},{"name":"Miyamoto Hiroshi"},{"name":"Gay Steffen"},{"name":"Pessler Frank"},{"name":"Shobuike Takeo"}],"ja":[{"name":"Kukita Akiko"},{"name":"Kukita Toshio"},{"name":"Nagata Kengo"},{"name":"寺町 順平"},{"name":"Li Yin-Ji"},{"name":"Yoshida Hiroki"},{"name":"Miyamoto Hiroshi"},{"name":"Gay Steffen"},{"name":"Pessler Frank"},{"name":"Shobuike Takeo"}]},"description":{"en":"Since transcription factors expressed in osteoclasts are possible targets for regulation of bone destruction in bone disorders, we investigated the expression of the transcription factor FBI-1/OCZF/LRF (in humans, factor that binds to inducer of short transcripts of human immunodeficiency virus type 1; in rats, osteoclast-derived zinc finger; in mice, leukemia/lymphoma-related factor) in patients with rheumatoid arthritis (RA), and assessed its role in osteoclastogenesis in vivo. Expression of FBI-1/OCZF was investigated in subchondral osteoclasts in human RA and in rat adjuvant-induced arthritis (AIA) using immunostaining and in situ hybridization, respectively. Transgenic mice overexpressing OCZF (OCZF-Tg) under the control of the cathepsin K promoter were generated, and bone mineral density and bone histomorphometric features were determined by peripheral quantitative computed tomography, calcein double-labeling, and specific staining for osteoclasts and osteoblasts. LRF/OCZF expression and the consequence of LRF inhibition were assessed in vitro with RANKL-induced osteoclast differentiation. FBI-1/OCZF was detected in the nuclei of osteoclasts in rat AIA and human RA. RANKL increased the levels of LRF messenger RNA and nuclear-localized LRF protein in primary macrophages. In OCZF-Tg mice, bone volume was significantly decreased, the number of osteoclasts, but not osteoblasts, was increased in long bones, and osteoclast survival was promoted. Conversely, inhibition of LRF expression suppressed the formation of osteoclasts from macrophages in vitro. FBI-1/OCZF/LRF regulates osteoclast formation and apoptosis in vivo, and may become a useful marker and target in treating disorders leading to reduced bone density, including chronic arthritis.","ja":"Since transcription factors expressed in osteoclasts are possible targets for regulation of bone destruction in bone disorders, we investigated the expression of the transcription factor FBI-1/OCZF/LRF (in humans, factor that binds to inducer of short transcripts of human immunodeficiency virus type 1; in rats, osteoclast-derived zinc finger; in mice, leukemia/lymphoma-related factor) in patients with rheumatoid arthritis (RA), and assessed its role in osteoclastogenesis in vivo. Expression of FBI-1/OCZF was investigated in subchondral osteoclasts in human RA and in rat adjuvant-induced arthritis (AIA) using immunostaining and in situ hybridization, respectively. Transgenic mice overexpressing OCZF (OCZF-Tg) under the control of the cathepsin K promoter were generated, and bone mineral density and bone histomorphometric features were determined by peripheral quantitative computed tomography, calcein double-labeling, and specific staining for osteoclasts and osteoblasts. LRF/OCZF expression and the consequence of LRF inhibition were assessed in vitro with RANKL-induced osteoclast differentiation. FBI-1/OCZF was detected in the nuclei of osteoclasts in rat AIA and human RA. RANKL increased the levels of LRF messenger RNA and nuclear-localized LRF protein in primary macrophages. In OCZF-Tg mice, bone volume was significantly decreased, the number of osteoclasts, but not osteoblasts, was increased in long bones, and osteoclast survival was promoted. Conversely, inhibition of LRF expression suppressed the formation of osteoclasts from macrophages in vitro. FBI-1/OCZF/LRF regulates osteoclast formation and apoptosis in vivo, and may become a useful marker and target in treating disorders leading to reduced bone density, including chronic arthritis."},"publication_date":"2011-09","publication_name":{"en":"Arthritis and Rheumatism","ja":"Arthritis and Rheumatism"},"volume":"Vol.63","number":"No.9","starting_page":"2744","ending_page":"2754","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1002/art.30455"],"issn":["1529-0131"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/21339747","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=263756","label":"url"}],"paper_title":{"en":"Adenosine abolishes MTX-induced suppression of osteoclastogenesis and inflammatory bone destruction in adjuvant-induced arthritis","ja":"Adenosine abolishes MTX-induced suppression of osteoclastogenesis and inflammatory bone destruction in adjuvant-induced arthritis"},"authors":{"en":[{"name":"Teramachi Jumpei"},{"name":"Kukita Akiko"},{"name":"Li Yin-Ji"},{"name":"Ushijima Yuki"},{"name":"Ohkuma Hiroshi"},{"name":"Wada Naohisa"},{"name":"Watanabe Toshiyuki"},{"name":"Nakamura Seiji"},{"name":"Kukita Toshio"}],"ja":[{"name":"寺町 順平"},{"name":"Kukita Akiko"},{"name":"Li Yin-Ji"},{"name":"Ushijima Yuki"},{"name":"Ohkuma Hiroshi"},{"name":"Wada Naohisa"},{"name":"Watanabe Toshiyuki"},{"name":"Nakamura Seiji"},{"name":"Kukita Toshio"}]},"description":{"en":"Methotrexate (MTX) is widely utilized for the treatment of patients with rheumatoid arthritis (RA); however, recent observation of the MTX-resistant patients proposed some difficulty in MTX-dependent therapeutic approach for RA. To access cellular events related to MTX resistance in RA in respect to inflammatory bone destruction, we investigated on an involvement of the potent inflammatory mediator adenosine in the regulation of osteoclastogenesis and inflammatory bone destruction. In rats with adjuvant-induced arthritis (AA rats), MTX efficiently suppressed bone destruction when it was administrated within 3 days after adjuvant injection, while it could not suppress inflammatory bone destruction if MTX was injected at the time of onset of inflammation (at day 10 after adjuvant injection). Time-course change in the level of plasma adenosine of AA rats was estimated by use of high-performance liquid chromatography and elucidated that adenosine level was markedly elevated till 10 days after adjuvant injection. In vitro bone marrow culture system for evaluating osteoclastogenesis, MTX markedly suppressed osteoclastogenesis in a stromal cell-dependent manner. This MTX-induced suppression of osteoclastogenesis was abrogated by the addition of adenosine. MTX suppressed the expression of mRNA for the receptor activator NF-κB ligand (RANKL), but it did not suppress the expression of osteoprotegerin (OPG). The addition of MTX and adenosine together markedly suppressed the level of OPG expression. Abolishment of MTX action by adenosine was significantly blocked by MRS1754, a highly selective antagonist for the A(2b) adenosine receptor (A(2b)AR), but not by caffeine, an antagonist for A1, A(2a), A3 AR (A1AR, A(2a)AR, and A3AR), which suggests that adenosine acts through A(2b)AR. Immunohistochemical studies showed abundant expression of A(2b)AR in cells localized in the bone-bone marrow boundary of the distal tibia in AA rats but not in control rats. When adenosine was injected in the ankle joints of MTX-treated AA rats, the suppressive effects of MTX on bone destruction was abolished. The current data therefore suggest that upregulation of adenosine production abolished the suppressive effect of MTX on osteoclastic bone destruction. Involvement of the adenosine-A(2b)AR system may explain MTX resistance in RA.","ja":"Methotrexate (MTX) is widely utilized for the treatment of patients with rheumatoid arthritis (RA); however, recent observation of the MTX-resistant patients proposed some difficulty in MTX-dependent therapeutic approach for RA. To access cellular events related to MTX resistance in RA in respect to inflammatory bone destruction, we investigated on an involvement of the potent inflammatory mediator adenosine in the regulation of osteoclastogenesis and inflammatory bone destruction. In rats with adjuvant-induced arthritis (AA rats), MTX efficiently suppressed bone destruction when it was administrated within 3 days after adjuvant injection, while it could not suppress inflammatory bone destruction if MTX was injected at the time of onset of inflammation (at day 10 after adjuvant injection). Time-course change in the level of plasma adenosine of AA rats was estimated by use of high-performance liquid chromatography and elucidated that adenosine level was markedly elevated till 10 days after adjuvant injection. In vitro bone marrow culture system for evaluating osteoclastogenesis, MTX markedly suppressed osteoclastogenesis in a stromal cell-dependent manner. This MTX-induced suppression of osteoclastogenesis was abrogated by the addition of adenosine. MTX suppressed the expression of mRNA for the receptor activator NF-κB ligand (RANKL), but it did not suppress the expression of osteoprotegerin (OPG). The addition of MTX and adenosine together markedly suppressed the level of OPG expression. Abolishment of MTX action by adenosine was significantly blocked by MRS1754, a highly selective antagonist for the A(2b) adenosine receptor (A(2b)AR), but not by caffeine, an antagonist for A1, A(2a), A3 AR (A1AR, A(2a)AR, and A3AR), which suggests that adenosine acts through A(2b)AR. Immunohistochemical studies showed abundant expression of A(2b)AR in cells localized in the bone-bone marrow boundary of the distal tibia in AA rats but not in control rats. When adenosine was injected in the ankle joints of MTX-treated AA rats, the suppressive effects of MTX on bone destruction was abolished. The current data therefore suggest that upregulation of adenosine production abolished the suppressive effect of MTX on osteoclastic bone destruction. Involvement of the adenosine-A(2b)AR system may explain MTX resistance in RA."},"publication_date":"2011-02-21","publication_name":{"en":"Laboratory Investigation; a Journal of Technical Methods and Pathology","ja":"Laboratory Investigation; a Journal of Technical Methods and Pathology"},"volume":"Vol.91","number":"No.5","starting_page":"719","ending_page":"731","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1038/labinvest.2011.9"],"issn":["1530-0307"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/21195346","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=263757","label":"url"}],"paper_title":{"en":"Contributions of the Measles Virus Nucleocapsid Gene and the SQSTM1/p62P392L Mutation to Paget's Disease","ja":"Contributions of the Measles Virus Nucleocapsid Gene and the SQSTM1/p62P392L Mutation to Paget's Disease"},"authors":{"en":[{"name":"Kurihara Noriyoshi"},{"name":"Hiruma Yuko"},{"name":"Yamana Kei"},{"name":"Michou Laëtitia"},{"name":"Rousseau Côme"},{"name":"Morissette Jean"},{"name":"Galson L. Deborah"},{"name":"Teramachi Jumpei"},{"name":"Zhou Hua"},{"name":"Dempster W. David"},{"name":"Windle J. Jolene"},{"name":"Brown P. Jacques"},{"name":"Roodman David G."}],"ja":[{"name":"Kurihara Noriyoshi"},{"name":"Hiruma Yuko"},{"name":"Yamana Kei"},{"name":"Michou Laëtitia"},{"name":"Rousseau Côme"},{"name":"Morissette Jean"},{"name":"Galson L. Deborah"},{"name":"寺町 順平"},{"name":"Zhou Hua"},{"name":"Dempster W. David"},{"name":"Windle J. Jolene"},{"name":"Brown P. Jacques"},{"name":"Roodman David G."}]},"description":{"en":"Paget's disease (PD) is characterized by abnormal osteoclasts (OCL) that secrete high IL-6 levels and induce exuberant bone formation. Because measles virus nucleocapsid gene (MVNP) and the p62(P392L) mutation are implicated in PD, marrows from 12 PD patients harboring p62(P392L) and eight normals were tested for MVNP expression and pagetic OCL formation. Eight out of twelve patients expressed MVNP and formed pagetic OCL in vitro, which were inhibited by antisense-MVNP. Four out of twelve patients lacked MVNP and formed normal OCL that were hyperresponsive to RANKL but unaffected by antisense-MVNP. Similarly, mice expressing only p62(P394L) formed normal OCL, while mice expressing MVNP in OCL, with or without p62(P394L), developed pagetic OCL and expressed high IL-6 levels dependent on p38MAPK activation. IL-6 deficiency in MVNP mice abrogated pagetic OCL development in vitro. Mice coexpressing MVNP and p62(P394L) developed dramatic Paget's-like bone lesions. These results suggest that p62(P394L) and IL-6 induction by MVNP play key roles in PD.","ja":"Paget's disease (PD) is characterized by abnormal osteoclasts (OCL) that secrete high IL-6 levels and induce exuberant bone formation. Because measles virus nucleocapsid gene (MVNP) and the p62(P392L) mutation are implicated in PD, marrows from 12 PD patients harboring p62(P392L) and eight normals were tested for MVNP expression and pagetic OCL formation. Eight out of twelve patients expressed MVNP and formed pagetic OCL in vitro, which were inhibited by antisense-MVNP. Four out of twelve patients lacked MVNP and formed normal OCL that were hyperresponsive to RANKL but unaffected by antisense-MVNP. Similarly, mice expressing only p62(P394L) formed normal OCL, while mice expressing MVNP in OCL, with or without p62(P394L), developed pagetic OCL and expressed high IL-6 levels dependent on p38MAPK activation. IL-6 deficiency in MVNP mice abrogated pagetic OCL development in vitro. Mice coexpressing MVNP and p62(P394L) developed dramatic Paget's-like bone lesions. These results suggest that p62(P394L) and IL-6 induction by MVNP play key roles in PD."},"publication_date":"2011-01-05","publication_name":{"en":"Cell Metabolism","ja":"Cell Metabolism"},"volume":"Vol.13","number":"No.1","starting_page":"23","ending_page":"34","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.cmet.2010.12.002"],"issn":["1932-7420"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/20728438","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=228454","label":"url"}],"paper_title":{"en":"Double stranded RNA-dependent protein kinase is involved in osteoclast differentiation of RAW264.7 cells in vitro","ja":"Double stranded RNA-dependent protein kinase is involved in osteoclast differentiation of RAW264.7 cells in vitro"},"authors":{"en":[{"name":"Teramachi Jumpei"},{"name":"Morimoto Hiroyuki"},{"name":"Baba Ryoko"},{"name":"Doi Yoshiaki"},{"name":"Hirashima Kanji"},{"name":"Haneji Tatsuji"}],"ja":[{"name":"寺町 順平"},{"name":"森本 景之"},{"name":"馬場 良子"},{"name":"土肥 良秋"},{"name":"平島 寛司"},{"name":"羽地 達次"}]},"description":{"en":"Double-stranded RNA-dependent protein kinase (PKR) plays a critical role in antiviral defence of the host cells. PKR is also involved in cell cycle progression, cell proliferation, cell differentiation, tumorigenesis, and apoptosis. We previously reported that PKR is required for differentiation and calcification of osteoblasts. However, it is unknown about the role of PKR in osteoclast differentiation. A dominant-negative PKR mutant cDNA, in which the amino acid lysine at 296 was replaced with arginine, was transfected into RAW264.7 cells. We have established the cell line that stably expresses the PKR mutant gene (PKR-K/R). Phosphorylation of PKR and α-subunit of eukaryotic initiation factor 2 was not stimulated by polyinosic-polycytidylic acid in the PKR-K/R cells. RANKL stimulated the formation of TRAP-positive multinuclear cells in RAW264.7 cells. However, TRAP-positive multinuclear cells were not formed in the PKR-K/R cells even when the cells were stimulated with higher doses of RANKL. A specific inhibitor of PKR, 2-aminopurine, also suppressed the RANKL-induced osteoclast differentiation in RAW264.7 cells. The expression of macrophage fusion receptor and dendritic cell-specific transmembrane protein significantly decreased in the PKR-K/R cells by real time PCR analysis. The results of RT-PCR revealed that the mRNA expression of osteoclast markers (cathepsin K and calcitonin receptor) was suppressed in the PKR-K/R cells and RAW264.7 cells treated with 2-aminopurine. Expression of NF-κB protein was suppressed in the PKR-K/R cells and 2-aminopurine-treated RAW264.7 cells. The level of STAT1 protein expression was elevated in the PKR-K/R cells compared with that of the wild-type cells. Immunohistochemical study showed that PKR was localized in osteoclasts of metatarsal bone of newborn mouse. The finding that the PKR-positive multinuclear cells should be osteoclasts was confirmed by TRAP-staining. Our present study indicates that PKR plays important roles in the differentiation of osteoclasts.","ja":"Double-stranded RNA-dependent protein kinase (PKR) plays a critical role in antiviral defence of the host cells. PKR is also involved in cell cycle progression, cell proliferation, cell differentiation, tumorigenesis, and apoptosis. We previously reported that PKR is required for differentiation and calcification of osteoblasts. However, it is unknown about the role of PKR in osteoclast differentiation. A dominant-negative PKR mutant cDNA, in which the amino acid lysine at 296 was replaced with arginine, was transfected into RAW264.7 cells. We have established the cell line that stably expresses the PKR mutant gene (PKR-K/R). Phosphorylation of PKR and α-subunit of eukaryotic initiation factor 2 was not stimulated by polyinosic-polycytidylic acid in the PKR-K/R cells. RANKL stimulated the formation of TRAP-positive multinuclear cells in RAW264.7 cells. However, TRAP-positive multinuclear cells were not formed in the PKR-K/R cells even when the cells were stimulated with higher doses of RANKL. A specific inhibitor of PKR, 2-aminopurine, also suppressed the RANKL-induced osteoclast differentiation in RAW264.7 cells. The expression of macrophage fusion receptor and dendritic cell-specific transmembrane protein significantly decreased in the PKR-K/R cells by real time PCR analysis. The results of RT-PCR revealed that the mRNA expression of osteoclast markers (cathepsin K and calcitonin receptor) was suppressed in the PKR-K/R cells and RAW264.7 cells treated with 2-aminopurine. Expression of NF-κB protein was suppressed in the PKR-K/R cells and 2-aminopurine-treated RAW264.7 cells. The level of STAT1 protein expression was elevated in the PKR-K/R cells compared with that of the wild-type cells. Immunohistochemical study showed that PKR was localized in osteoclasts of metatarsal bone of newborn mouse. The finding that the PKR-positive multinuclear cells should be osteoclasts was confirmed by TRAP-staining. Our present study indicates that PKR plays important roles in the differentiation of osteoclasts."},"publication_date":"2010-08-20","publication_name":{"en":"Experimental Cell Research","ja":"Experimental Cell Research"},"volume":"Vol.316","number":"No.19","starting_page":"3254","ending_page":"3262","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.yexcr.2010.08.006"],"issn":["1090-2422"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/19015643","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=263758","label":"url"}],"paper_title":{"en":"A possible suppressive role of galectin-3 in upregulated osteoclastogenesis accompanying adjuvant-induced arthritis in rats","ja":"A possible suppressive role of galectin-3 in upregulated osteoclastogenesis accompanying adjuvant-induced arthritis in rats"},"authors":{"en":[{"name":"Li Yin-Ji"},{"name":"Kukita Akiko"},{"name":"Teramachi Jumpei"},{"name":"Nagata Kengo"},{"name":"Wu Zhou"},{"name":"Akamine Akifumi"},{"name":"Kukita Toshio"}],"ja":[{"name":"Li Yin-Ji"},{"name":"Kukita Akiko"},{"name":"寺町 順平"},{"name":"Nagata Kengo"},{"name":"Wu Zhou"},{"name":"Akamine Akifumi"},{"name":"Kukita Toshio"}]},"description":{"en":"Galectin-3 is a beta-galactoside-binding animal lectin having pleiotropic effects on cell growth, differentiation, and apoptosis. This lectin has been shown to be involved in phagocytosis by macrophages and in inflammation. Here we investigated an involvement of galectin-3 in the regulatory process of inflammatory bone resorption in rats with adjuvant-induced arthritis (AA rats) accompanying severe bone destruction in the ankle joints. The protein level of galectin-3 in the ankle-joint extracts was markedly augmented at week 3 after adjuvant injection, at the time when severe bone destruction was observed. Immunohistochemical analysis revealed an extremely high expression of galectin-3 in macrophages and granulocytes infiltrated in the area of severe bone destruction. To estimate the role of galectin-3 in osteoclastogenesis and osteoclastic bone resorption, recombinant galectin-3 was added to in vitro culture systems. Galectin-3 markedly inhibited the formation of osteoclasts in cultures of murine osteoclast precursor cell line as well as in rat bone marrow culture systems. This inhibition was not observed by heat-inactivated galectin-3 or by galectin-7. Although recombinant galectin-3 did not affect signaling through mitogen-activated protein kinase (MAPK) or nuclear factor-kappaB (NF-kappaB), it specifically suppressed the induction of nuclear factor of activated T-cells c1 (NFATc1). Galectin-3 significantly inhibited dentine resorption by mature osteoclasts in vitro. Furthermore, in vivo studies clearly showed a significant suppression of bone destruction and osteoclast recruitment accompanying arthritis, when galectin-3 was injected into the cavity of ankle joint of AA rats. Thus, abundant galectin-3 observed in the area of severe bone destruction may act as a negative regulator for the upregulated osteoclastogenesis accompanying inflammation to prevent excess bone destruction.","ja":"Galectin-3 is a beta-galactoside-binding animal lectin having pleiotropic effects on cell growth, differentiation, and apoptosis. This lectin has been shown to be involved in phagocytosis by macrophages and in inflammation. Here we investigated an involvement of galectin-3 in the regulatory process of inflammatory bone resorption in rats with adjuvant-induced arthritis (AA rats) accompanying severe bone destruction in the ankle joints. The protein level of galectin-3 in the ankle-joint extracts was markedly augmented at week 3 after adjuvant injection, at the time when severe bone destruction was observed. Immunohistochemical analysis revealed an extremely high expression of galectin-3 in macrophages and granulocytes infiltrated in the area of severe bone destruction. To estimate the role of galectin-3 in osteoclastogenesis and osteoclastic bone resorption, recombinant galectin-3 was added to in vitro culture systems. Galectin-3 markedly inhibited the formation of osteoclasts in cultures of murine osteoclast precursor cell line as well as in rat bone marrow culture systems. This inhibition was not observed by heat-inactivated galectin-3 or by galectin-7. Although recombinant galectin-3 did not affect signaling through mitogen-activated protein kinase (MAPK) or nuclear factor-kappaB (NF-kappaB), it specifically suppressed the induction of nuclear factor of activated T-cells c1 (NFATc1). Galectin-3 significantly inhibited dentine resorption by mature osteoclasts in vitro. Furthermore, in vivo studies clearly showed a significant suppression of bone destruction and osteoclast recruitment accompanying arthritis, when galectin-3 was injected into the cavity of ankle joint of AA rats. Thus, abundant galectin-3 observed in the area of severe bone destruction may act as a negative regulator for the upregulated osteoclastogenesis accompanying inflammation to prevent excess bone destruction."},"publication_date":"2009-11","publication_name":{"en":"Laboratory Investigation; a Journal of Technical Methods and Pathology","ja":"Laboratory Investigation; a Journal of Technical Methods and Pathology"},"volume":"Vol.89","number":"No.1","starting_page":"26","ending_page":"37","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1038/labinvest.2008.111"],"issn":["1530-0307"]},"published_paper_type":"scientific_journal"},"priority":"input_data"} {"insert":{"type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/16205940","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-32444432178&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=263759","label":"url"}],"paper_title":{"en":"Regulation of osteoclastogenesis by Simon extracts composed of caffeic acid and related compounds: successful suppression of bone destruction accompanied with adjuvant-induced arthritis in rats","ja":"Regulation of osteoclastogenesis by Simon extracts composed of caffeic acid and related compounds: successful suppression of bone destruction accompanied with adjuvant-induced arthritis in rats"},"authors":{"en":[{"name":"Tang Quan Yong"},{"name":"Kukita Toshio"},{"name":"Ushijima Yuki"},{"name":"Kukita Akiko"},{"name":"Nagata Kengo"},{"name":"Sandra Ferry"},{"name":"Watanabe Toshiyuki"},{"name":"Toh Kazuko"},{"name":"Okuma Yutaka"},{"name":"Kawasaki Sadamichi"},{"name":"Rasubala Linda"},{"name":"Teramachi Jumpei"},{"name":"Miyamoto Ichiko"},{"name":"Wu Zhou"},{"name":"Iijima Tadahiko"}],"ja":[{"name":"Tang Quan Yong"},{"name":"Kukita Toshio"},{"name":"Ushijima Yuki"},{"name":"Kukita Akiko"},{"name":"Nagata Kengo"},{"name":"Sandra Ferry"},{"name":"Watanabe Toshiyuki"},{"name":"Toh Kazuko"},{"name":"Okuma Yutaka"},{"name":"Kawasaki Sadamichi"},{"name":"Rasubala Linda"},{"name":"寺町 順平"},{"name":"Miyamoto Ichiko"},{"name":"Wu Zhou"},{"name":"Iijima Tadahiko"}]},"description":{"en":"Simon extracts are vitamin K(1)-rich food materials extracted from the leaves of the Simon sweet potato. Although vitamin K is known to stimulate bone formation, we postulated that Simon extracts also contain unknown biological compounds having the ability to regulate bone resorption. Here we prepared the vitamin K-free fraction from the Simon extracts and investigated the ability of this fraction on the differentiation of osteoclasts. A remarkable inhibitory effect of osteoclastogenesis was observed when osteoclast precursors were treated with this fraction in rat bone marrow culture systems as well as in a pure differentiation system using murine osteoclast precursor cell line. The vitamin K-free Simon extracts markedly suppressed severe bone destruction mediated by abundant osteoclasts associated with adjuvant-induced arthritis in rats. High performance liquid chromatography (HPLC) analysis revealed that the vitamin K-free Simon extracts contained three types of low molecular weight inhibitors for osteoclastogenesis; caffeic acid, chlorogenic acids and isochlorogenic acids. Among these substances, caffeic acid showed the most powerful inhibitory effects on osteoclastogenesis. Caffeic acid significantly suppressed expression of NFATc1, a key transcription factor for the induction of osteoclastogenesis. Our current study enlightened a high utility of the Simon extracts and their chemical components as effective regulators for bone resorption accompanied with inflammation and metabolic bone diseases.","ja":"Simon extracts are vitamin K(1)-rich food materials extracted from the leaves of the Simon sweet potato. Although vitamin K is known to stimulate bone formation, we postulated that Simon extracts also contain unknown biological compounds having the ability to regulate bone resorption. Here we prepared the vitamin K-free fraction from the Simon extracts and investigated the ability of this fraction on the differentiation of osteoclasts. A remarkable inhibitory effect of osteoclastogenesis was observed when osteoclast precursors were treated with this fraction in rat bone marrow culture systems as well as in a pure differentiation system using murine osteoclast precursor cell line. The vitamin K-free Simon extracts markedly suppressed severe bone destruction mediated by abundant osteoclasts associated with adjuvant-induced arthritis in rats. High performance liquid chromatography (HPLC) analysis revealed that the vitamin K-free Simon extracts contained three types of low molecular weight inhibitors for osteoclastogenesis; caffeic acid, chlorogenic acids and isochlorogenic acids. Among these substances, caffeic acid showed the most powerful inhibitory effects on osteoclastogenesis. Caffeic acid significantly suppressed expression of NFATc1, a key transcription factor for the induction of osteoclastogenesis. Our current study enlightened a high utility of the Simon extracts and their chemical components as effective regulators for bone resorption accompanied with inflammation and metabolic bone diseases."},"publication_date":"2006-03","publication_name":{"en":"Histochemistry and Cell Biology","ja":"Histochemistry and Cell Biology"},"volume":"Vol.125","number":"No.3","starting_page":"215","ending_page":"225","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1007/s00418-005-0062-4"],"issn":["0948-6143"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}