2019 Fiscal Year Final Research Report
Mechano-sensor TRPV2 is involved in lubricin induction and suppression of ectopic endochondral ossification in articular joints
| Project/Area Number |
17K10997
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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 |
Kawaguchi Kohei 東京大学, 大学院総合文化研究科, 特任研究員 (40794227)
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| Co-Investigator(Kenkyū-buntansha) |
齋藤 琢 東京大学, 医学部附属病院, 准教授 (30456107)
武冨 修治 東京大学, 医学部附属病院, 講師 (70570018)
張 成虎 東京大学, 医学部附属病院, 助教 (80780551)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Keywords | 変形性膝関節症 / メカノセンシティブイオンチャネル / Trpv2 |
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| Outline of Final Research Achievements |
TRPV2 plays a role in mediating intracellular Ca2+ current via mechanical stimuli in several organs. Here, we investigated the involvement of TRPV2 in mouse articular chondrocytes. The Trpv2 protein was detected in the superficial zone of the articular cartilage in adult mice. OA development and heterotopic ossification were accelerated in chondrocyte specific Trpv2 knockout mice. The link between TRPV2 -mediated Ca2+ influx and FFSS-dependent lubricin induction was further supported by experiments with cultured chondrocyte isolated from Trpv2 knockout mice. The activity of CREB was increased by TRPV2 agonist 2APB treatment. In contrast, KN93 mediated inhibition of calmodulin reduced the enhanced activity of CREB by 2APB treatment.Thus, TRPV2 contributes to protection on articular cartilage by inducing lubricin via the CaM/CREB pathway. In addition, Trpv2 may suppress osteophyte formation during OA development by suppressing hypertrophic differentiation via Calcineurin/Nfatc1 patyway.
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| Free Research Field |
整形外科学
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| Academic Significance and Societal Importance of the Research Achievements |
変形性関節症は遺伝的要因、代謝疾患要因、環境的要因、そして力学的負荷など様々な要因からなる多因子疾患であるが、中でも過度の体重増加もしくは過度の運動などが高いリスクであることから、過剰な力学的負荷は変形性関節症の最大の誘因と考えられている。そこで、関節軟骨に発現している、メカノセンシティブイオンチャネルの候補分子としてTRPV2に着目した。Trpv2は機械的刺激依存性に軟骨細胞の肥大分化を抑制し、変形性関節症進行における異所性骨化を抑制している可能性が示唆されたことより、Trpv2の機能解析が進めば変形性関節症の治療の有力なターゲットとしての可能性が期待される。
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