FGF9在关节软骨稳态维持及OA中的作用与机制研究

Osteoarthritis (OA) is a frequently-occurred disease in the elderly, which mainly affects the weight-bearing joints, causing dysfunction. There is no effective drug for OA. Abnormally increased degradation of extracellular matrix and premature differentiation of chondrocytes are two important pathogenic factors in OA. FGF9 plays an important role in regulating the endochondral ossification and joint development. We recently found that intra-articular injection of FGF9 can relieve the articular cartilage degeneration of OA mice, but the underlying mechanism is still unclear, and studies have indicated that there is crosstalk between FGF9 and Wnt/β-Catenin in multiple tissues including the cartilage. In order to identify the role of FGF9 in the maintainence of articular cartilage homeostasis in vivo, we will employ inducible chondrocyte-specific knockout or overexpression of FGF9 or β-Catenin mouse models and TOP-gal reporter mice,by making OA model in these mouse strains, to dissect the roles of FGF9 in the maintainence of articular cartilage homeostasis and the role of β-Catenin in it. This study will clarify the role and mechanism of FGF9 in the regulating the homeostasis of articular cartilage, providing the experimental data for the development of FGF9-based drugs against OA.

骨性关节炎（OA）是中老年人常见多发病，多累及负重关节，导致功能障碍，目前没有有效安全的防治药物，严重影响人类健康。关节软骨细胞外基质代谢异常与软骨细胞异常肥大分化是OA的两个重要致病因素。FGF9是调控软骨内成骨及关节发育的重要调控分子，前期我们发现FGF9关节内注射可以缓解小鼠OA模型的关节软骨损伤退变，但具体机制不清楚，有报道提示FGF9与Wnt/β-Catenin在多个组织包括软骨中存在串话。为进一步在整体动物水平明确FGF9在关节软骨稳态维持及OA发生中的作用及机制，我们将利用在软骨细胞可诱导敲除或增强FGF9以及Wnt/β-Catenin的小鼠模型与TOP-gal报道小鼠，结合小鼠OA模型，研究FGF9在小鼠关节软骨稳态维持及OA发生中的作用，并明确Wnt/β-Catenin等信号分子在其中的作用。本研究将揭示FGF9在关节软骨稳态维持中的作用与机制，为研发基于FGF9的防治。

骨性关节炎（OA）是中老年人常见多发病，多累及负重关节，导致功能障碍，目前缺乏有效安全的防治药物，严重影响人类健康。关节软骨细胞外基质代谢异常与软骨细胞异常肥大分化是OA的两个重要致病因素。探讨其发生机制，可望寻找基于机制的生物治疗措施。. FGF9是调控软骨内成骨及关节发育的重要调控分子，可能参与关节稳态及OA的发生。本课题中我们发现DMM后小鼠关节软骨的FGF9表达明显下降；关节腔内注射外源性FGF9能明显缓解DMM手术所导致的关节软骨基质丢失，肥大标记分子Collagen X和基质降解酶MMP13的表达升高；在人关节软骨组织培养模型中，外源性FGF9能显著缓解IL-1β刺激所导致的软骨基质丢失，Collagen X和MMP13的表达升高等；关节腔内注射外源性FGF9会导致DMM手术所致的小鼠关节骨赘形成增加，与关节骨赘处细胞PCNA，SOX9和Collagen II的表达升高相关。成年小鼠软骨中可诱导敲除FGF9对关节稳态维持及创伤后骨性关节炎的发生、进展无明显影响，相关软骨代谢与野生小鼠类似。成年小鼠成骨中可诱导敲除FGF9不引起软骨稳态的变化，但可造成骨量减少及骨骼中血管形成降低。.