FHL2及INPP4B对软骨下骨TGFβ信号通路的影响及其在骨关节炎中的作用机制研究

骨性关节炎（osteoarthritis,OA）严重影响患者的生活质量，甚至造成残疾。其分子机制仍尚未清楚。近年来，TGF-β1信号通路对OA发病机制中的作用日益得到重视，且我们的前期研究结果表明阻断TGF-β1信号通路明显延缓OA的进展。我们前期转录组测序结果显示OA软骨下骨中TGF-β1及INPP4B表达水平增高，而FHL2的表达水平减少，但其在OA发病中的作用机制尚待进一步深入研究。我们依据先前的实验结果及文献提出假说：FHL2对TGF-β1信号通路的负调控作用及INPP4B增强TGFβ信号通路的传导及活性在OA的发生发展中起了重要作用。为了验证这一假说，我们通过MSC迁移实验和FHL2、INPP4B基因条件性敲除小鼠OA模型，从分子、细胞及动物水平阐明FHL2、INPP4B在OA发病中的作用靶点及其对TGF-β信号通路的调控在OA发病中的分子机制，为治疗OA提供新思路及干预靶点。

Osteoarthritis (OA) seriously affects the quality of life of patients, even causes disability. Its molecular mechanism is still unclear. In recent years, more and more attention has been paid to the role of TGF-β1 signaling pathway in the pathogenesis of OA. Our transcriptome sequencing results showed tha TGF-β1,INPP4B expression levels increased, while FHL2 expression level decreased in subchondral bone of OA.however,the mechanism of its role in the pathogenesis of OA needs further study. Based on the previous experimental results and literature, we hypothesized that FHL2 negatively regulates the TGF-β1 signaling pathway and INPP4B enhances the conduction and activity of TGF-β1 signaling pathway plays an important role in the occurrence and development of OA. In order to test this hypothesis, we intend to use MSC migration experiment and OA model of FHL2 and INPP4B gene conditionally knockout mice to elucidate the molecular mechanism of FHL2 and INPP4B in the pathogenesis of OA and their regulation of TGF-β1 signaling pathway in the pathogenesis of OA at the molecular, cellular and animal levels, so as to provide new ideas and intervention targets for the treatment of OA.