2019 Fiscal Year Final Research Report
Elucidation of regulatory mechanism for RANKL-dependent osteo-network by transcriptional factor complex analysis
| Project/Area Number |
17K09892
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Endocrinology
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| Research Institution | Toho University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
小出 尚史 千葉大学, 医学部附属病院, 助教 (30507223)
鈴木 佐和子 千葉大学, 医学部附属病院, 助教 (60400892)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Keywords | 骨リモデリング / 破骨 / 分化 / 遺伝子 / ゲノム / 発現制御 / エピゲノム |
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| Outline of Final Research Achievements |
Nuclear factor of activated T-cell cytoplasmic 1 (NFATc1) is a master regulator of osteoclast differentiation induced by RANKL, which is a pivotal cytokine for osteoclast differentiation. We identified novel epigenetic/chromatin regulatory molecules and wolf-Hirschhorn syndrome candidate 1 (WHSC1) as NFATc1 interaction proteins using tandem affinity purification followed by LC-MS / MS analysis. WHSC1 is a histone H3-K36 methyltransferase, and its mutations in human is known to cause abnormal cartilage and bone. Then we created WHSC1 and RANKL knockout cells by CRISPR / Cas9 system. And revealed that both of knockout cells showed decreasing osteoclast differentiation-related genes after RANKL stimulation. Further, WHSC1 and RANKL mutually suppressed transcription. This study clarified one of the regulatory systems of complex differentiation process in osteoclasts, which mediated by WHSC1 in the RANKL-NFATc1 complexes in response to various upstream signals.
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| Free Research Field |
内分泌学
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| Academic Significance and Societal Importance of the Research Achievements |
骨粗鬆症治療において様々な治療薬の選択が可能となってきたが、骨吸収抑制を主体とした薬剤は、特に骨形成まで抑制してしまう問題もあり、破骨細胞による骨芽細胞機能維持機能を保持しながら過剰な骨吸収を抑制することのできる薬剤開発が望まれる。本研究でRANKL 依存的骨ネットワーク制御における特定のシグナルをモジュレートする新たな制御機構を解明することが出来た。更に破骨細胞内で発現時期や機能の異なる遺伝子の発現調節を行うメカニズムとしてNFATc1を中心とするepigenetic mechanisms を明らかとし骨エピジェネティクス制御の解明に役立つと共に、創薬基盤の開発に繋がることが期待される。
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