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en: Mechanisms of preferential bone formation in myeloma bone lesions by proteasome inhibitors.

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.

en: International Journal of Hematology

ja: International Journal of Hematology


en: The Xanthine Oxidase Inhibitor Febuxostat Suppresses Adipogenesis and Activates Nrf2.

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.

en: Antioxidants

ja: Antioxidants


en: Aberrant upregulation of the endogenous PP2A inhibitor CIP2A is vital for myeloma cell growth and survival

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.

en: International Journal of Myeloma

ja: International Journal of Myeloma


en: Alveolar corticotomy for extrusion of an ankylosed lower first molar.

en: Journal of Clinical Orthodontics

ja: Journal of Clinical Orthodontics


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.

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.

en: Clinical & translational immunology

ja: Clinical & translational immunology


en: TAK1 is a pivotal therapeutic target for tumor progression and bone destruction in myeloma

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.

en: Haematologica

ja: Haematologica


en: Surgical orthodontic treatment of skeletal mandibular protrusion with multiple impacted ankylosed teeth treated with alveolar corticotomy

en: To present a case of skeletal mandibular protrusion with multiple impacted ankylosed teeth, which were treated with conventional orthognathic surgery and alveolar corticotomy, respectively. Tooth ankylosis is characterized by the fusion of a root surface with the surrounding alveolar bone. Various treatment modalities for tooth ankylosis have been developed and are used commonly in the clinic. Corticotomy is defined as the application of intentional surgical injury to the cortical bone to mobilize a tooth with the adjacent bone and soft tissues. The corticotomy technique has been improved in recent years to avoid possible risks such as periodontal damage, tooth devitalization, and osseous necrosis due to an inadequate blood supply. A female patient aged 16 years and 3 months was diagnosed with anterior crossbite and the impaction and ankylosis of multiple canines. After the confirmation of ankylosis, alveolar corticotomy was performed on the maxillary left and mandibular right canines. After 6 months of traction (patient age, 19 years and 7 months), both canines had extruded successfully. After the completion of preoperative treatment, bilateral intraoral vertical ramus osteotomy was performed to correct the anterior crossbite involving a skeletal mandibular protrusion. The amounts of mandibular setback on the right and left sides were approximately 7 and 5 mm, respectively. The total treatment period was 55 months. Acceptable occlusion with a balanced profile was maintained over a 5-year retention period, indicating the long-term stability and success of the treatment. Our results indicate that alveolar corticotomy should be considered to facilitate the treatment of multiple impacted ankylosed teeth. This report proposes an efficacy of alveolar corticotomy for extrusion of impacted ankylosed teeth.

en: The Journal of Contemporary Dental Practice


en: 徳島大学病院矯正歯科における保険診療に関する実態調査-先天性疾患における裂奇形の併発について

en: 矯正歯科治療に健康保険が導入されて約40年が経過し，唇顎口蓋裂と顎変形症の他に2018年現在53項目が保険治療の対象になっている．今回，我々は当科における矯正歯科治療の保険適用患者の実態を調査し，特に唇顎口蓋裂と他の先天性疾患との関連性について臨床統計学的検討を行ったので報告する．徳島大学病院病院情報システム・データウェアハウスを用い，2008年1月から2018年12月までの11年間に当院矯正歯科を受診した患者から保険治療を受けている患者を抽出し，顎変形症単独症例を除く先天性疾患患者について，電子カルテ全文検索システムを用いて臨床統計学的検討を行った．研究対象期間に当科にて保険治療を受けた矯正患者は345人で，そのうち，本研究対象患者は，顎変形症単独症例を除く207人であった．患者の内訳は，裂奇形を主徴候とする症例が全体の5割を占め最も多く，次いで，6歯以上の先天性部分性無歯症，ゴールデンハー症候群(鰓弓異常症を含む)，ダウン症候群の順であった．また，症候性疾患の中で裂奇形の併発は，ピエール・ロバン症候群，ダウン症候群，ゴールデンハー症候群の順に多く，その裂型は，口蓋裂(軟口蓋裂を含む)，唇顎口蓋裂，唇裂の順に多かった．以上のことから，当病院は裂奇形を併発した先天性疾患への専門的な対応が不可欠であり，希少疾患にも柔軟に対応できるよう複数の診療科，職種による診療科の枠組みを超えたチーム医療体制の構築が必要であることが示唆された．

en: The Journal of Chu-Shikoku Orthodontic Society

ja: 中·四国矯正歯科学会雑誌


en: The Roles of ROS Generation in RANKL-Induced Osteoclastogenesis: Suppressive Effects of Febuxostat.

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.

en: Cancers

ja: Cancers