| Project/Area Number |
18K08465
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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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| Review Section |
Basic Section 54040:Metabolism and endocrinology-related
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| Research Institution | Chiba University |
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Principal Investigator |
Koide Hisashi 千葉大学, 大学院医学研究院, 特任准教授 (30507223)
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| Co-Investigator(Kenkyū-buntansha) |
田中 知明 千葉大学, 大学院医学研究院, 教授 (50447299)
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| Project Period (FY) |
2018-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2022: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
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| Keywords | 骨代謝 / 骨粗鬆症 / 骨リモデリング / 骨形成 / Rhoシグナル / Wntシグナル / 骨芽細胞 / メカニカルストレス |
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| Outline of Final Research Achievements |
Previous research has suggested the involvement of AKAP13 in the early stages of osteogenesis. Conditional knockout of Akap13 in the bone resulted in osteoporotic changes in mice. Akap13 overexpression in MC3T3-E1 cells increased the nuclear translocation of β-catenin via Wnt3a induction. Akap13 depletion led to significant decreases in Lef1 mRNA expression in MC3T3-E1 cells. Overexpression of Akap13 in MC3T3-E1 cells increased RhoA activity, but this was not observed for the Akap13 mutant lacking the guanine nucleotide exchange factor domain. Overexpression of Akap13 increased Alp mRNA levels. RhoA overexpression in immortalized bone marrow-derived stromal cells resulted in Alp mRNA upregulation in a RhoA induction-dependent manner. Wnt3a-induced β-catenin nuclear translocation was inhibited by Rho inhibitor in Akap13-overexpressed MCT3-E1 cells. Overall, these results suggest that AKAP13 plays an important role in regulating osteogenesis through Wnt signaling pathways.
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| Academic Significance and Societal Importance of the Research Achievements |
RhoAシグナルは骨芽細胞の分化調節に重要であることは論を俟たない。また、臨床レベルでAKAPファミリー分子が骨粗鬆症との関連を示唆する報告を認めるが、我々が世界で初めてAKAPの骨での役割を基礎研究レベルで明らかにした。Rho-GEFのAKAP13は骨形成に作用し、Akap13コンディショナルノックアウトマウスは骨粗鬆症様変化を認め、Akap13はRhoA活性化を介した経路により、Wnt3a誘導性b-カテニンの核内移行やLef1遺伝子を制御し、骨芽細胞の増殖分化を制御している可能性が示唆された。様々なシグナルを統合するAkap13の機能を通じて、骨粗鬆症治療の創薬に繋がることが期待される。
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