| Project/Area Number |
17K10998
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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 |
Orthopaedic surgery
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Fujii Tomoko 東京大学, 医学部附属病院, 特任講師 (40793089)
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| Co-Investigator(Kenkyū-buntansha) |
山神 良太 東京大学, 医学部附属病院, 特任臨床医 (00722191)
矢野 文子 東京大学, 医学部附属病院, 特任准教授 (80529040)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | 変形性膝関節症 / Wntシグナル / βcatenin / 関節軟骨 / Prg4 / メカニカルストレス / ルブリシン / Wnt-βcatenin / 関節軟骨最表層 |
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| Outline of Final Research Achievements |
In SFZ-specific β-catenin-knockout mice, OA development was significantly accelerated, which was accompanied by decreased Prg4 expression and SFZ destruction. In contrast, Prg4 expression was enhanced and cartilage degeneration was suppressed in SFZ-specific β-catenin-stabilized mice. In primary SFZ cells, Prg4 expression was downregulated by β-catenin knockout, while it was upregulated by β-catenin stabilization by exon 3 deletion or treatment with CHIR99021. Among Wnt ligands, Wnt5a, Wnt5b, and Wnt9a were highly expressed in SFZ cells, and recombinant human WNT5A and WNT5B stimulated Prg4 expression. Mechanical loading upregulated expression of these ligands and further promoted Prg4 transcription. Moreover, mechanical loading and Wnt/β-catenin signaling activation increased mRNA levels of Creb1, a potent transcription factor for Prg4.
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| Academic Significance and Societal Importance of the Research Achievements |
Wnt-βcateninシグナルの関節軟骨最表層の保持と制御機構への関わりを生理的条件下で解明すべく、それぞれの組織・時期特異的ノックアウトマウスとトランスジェニックマウスについて変形性関節症（OA)モデルを解析した。
そのメカニズムを解明することは、関節軟骨の維持、変性予防効果のあるWnt-βcatenin修飾化合物を同定し、有望なものについてはマウスモデル上での変形性膝関節症の治療効果の検討を行い、OA新規治療候補薬の開発に繋ぐ。
Wnt-βcateninシグナルを臨床応用した場合の効果だけでなく、副作用を予期する上でも必要であり、OAの新規治療法開発に大いに貢献することは間違いない。
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