Fyn活化在骨关节炎中的作用及其机制研究

Osteoarthritis (OA) is the most common joint disease characterized by a loss of articular cartilage. However, the underlying mechanisms of cartilage loss and OA development have not yet been fully elucidated. There is also lack of effective therapy methods in clinic. Src family tyrosine kinase (SFKs) serves as a central regulator of cell growth and proliferation, but its role in OA development needs further investigation. Our preliminary results demonstrate that Fyn, As one major member of SFKs, is highly upregulated and activated in OA articular chondrocytes, inhibition of Fyn alleviated cartilage degeneration and loss in OA, implicating an important of Fyn in the pathogenesis of OA. Using Fyn knockout mice and OA mice as models, combined with samples of OA patients and normal population, this project aims to investigate the role and regulation mechanism of chondrocyte Fyn in the pathogenesis of OA on the molecular, cellular and animal levels. The study will provide potential target for prevention and treatment of OA.

骨关节炎（Osteoarthritis，OA）是最常见的关节疾病，关节软骨破坏是其最明显的病理特征，然而关节软骨破坏及骨关节炎的发病机理尚未阐明，临床上缺乏有效的防治方法。Src蛋白激酶家族（Src family tyrosine kinase, SFKs）是调控软骨细胞增殖分化的关键信号分子，但其活性改变在骨关节炎发生发展中的作用有待研究。我们的前期研究发现，作为SFKs家族重要成员之一的Fyn在骨关节炎关节软骨中表达水平明显上调，抑制其活性能显著缓解骨关节炎进程，提示关节软骨细胞中Fyn活性改变可能在骨关节炎发生与发展中起重要作用。本课题拟通过临床标本、Fyn全身敲除小鼠模型以及可诱导型软骨细胞特异性敲除小鼠模型，深入探讨软骨细胞Fyn活性改变在骨关节炎病程中的作用及其分子机制，为防治骨关节炎提供新的潜在靶点。

骨关节炎(OA)是一种与年龄相关的退行性关节疾病，多个病理改变参与了疾病进展。由于其发病机制还未完全阐明，目前可以有效延缓软骨退变的治疗方法十分有限。在本研究中，我们首先发现了伴随软骨退变的同时，酪氨酸激酶Fyn在老年小鼠、实验性OA小鼠和人OA软骨关节软骨细胞中表达上调，同时高水平表达的Fyn进一步激活β-catenin信号通路，促进β-catenin的核易位并诱导与OA相关基因的表达。与对照组小鼠相比，基因敲除Fyn后可以延缓创伤诱导后OA的发生。Src家族激酶(SFKs)抑制剂AZD0530和Fyn PP1抑制剂通过抑制β-catenin活性进一步降低关节软骨中分解代谢酶的表达水平从而延缓OA进展。因此，在OA进展中Fyn表达升高并激活β-catenin信号，进一步加速软骨的退变，靶向Fyn可能是治疗OA的一种有效方法，现有药物AZD0530和PP1的应用适应症可能会得到新的扩展。