| Project/Area Number |
18H02926
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 56020:Orthopedics-related
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| Research Institution | Kyoto University |
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Principal Investigator |
Murata Koichi 京都大学, 医学研究科, 特定助教 (60806793)
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| Co-Investigator(Kenkyū-buntansha) |
吉富 啓之 京都大学, 医学研究科, 准教授 (50402920)
寺尾 知可史 国立研究開発法人理化学研究所, 生命医科学研究センター, チームリーダー (60610459)
伊藤 宣 京都大学, 医学研究科, 特定教授 (70397537)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000)
Fiscal Year 2020: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2018: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
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| Keywords | 破骨細胞 / 低酸素 / 関節リウマチ / 骨粗鬆症 / 炎症性疾患 / SNP |
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| Outline of Final Research Achievements |
The purpose of this study was to comprehensively elucidate the mechanism of promoting osteoclast differentiation under hypoxia and to search for a therapeutic method for bone destruction specific to rheumatoid arthritis. We found that KDM1a is important using specific siRNAs and inhibitors. KDM1a is mTOR-dependently induced by RANKL stimulation during osteoclastogenesis. KDM1a regulated metabolism in HIF1-mediated osteoclast differentiation not only under hypoxia but also under normoxia. Furthermore, it regulated the expression of E2F1 regulating the cell cycle and metabolism in osteoclast differentiation. The HIF-mediated osteoclast differentiation pathway of KDM1a was found to be important in inflammatory bone resorption, including rheumatoid arthritis.
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| Academic Significance and Societal Importance of the Research Achievements |
関節リウマチは炎症性疾患で、骨軟骨破壊を来して、機能障害を引き起こす。近年様々な薬剤が開発されたものの、骨破壊は完全には制御できておらず、既存の治療は副作用や長期使用に問題がある。今回、骨を破壊する細胞の主軸である破骨細胞の分化において、KDM1aが重要であることが分かった。KDM1aを介した炎症部位特異的な骨破壊の機序が明らかになり、今後関節リウマチの新たな骨破壊の治療法になる可能性がある。
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