探讨骨关节炎中GDF-5/ Smad/C-1-1信号通路介导的表观遗传学改变及调控机制研究

骨关节炎是基因与环境因素共同作用、多因子参与的复杂性过程。前期的研究表明GDF-5和C-1-1在调控软骨发育和维持软骨细胞永久性表型过程中起着关键作用。表观遗传是连接环境因素和基因相互作用的桥梁，GDF-5/Smad/C-1-1通路的异常表观遗传修饰与骨关节疾病的发生发展密切相关，但至今尚无研究证实。本研究拟通过OA模型，采用免疫沉淀＋芯片技术，研究OA不同病理阶段GDF-5/Smad/C-1-1 信号通路的活性，及其关键因子的基因甲基化和组蛋白乙酰化改变，明确上述变化是否会引起GDF-5/Smad/C-1-1通路抑制，继而导致关节软骨细胞发生退变表型。并运用特异性干预手段，改变GDF-5/Smad/C-1-1通路异常的表观遗传修饰，尝试缓解或逆转OA，从而深入探讨表观遗传修饰抑制GDF-5/Smad/C-1-1 信号通路在OA发病机制中的作用。为OA的临床早期诊断和治疗提供新的思路。

Osteoarthritis has a complex developmental process that the genetic and environmental factors and multiple factors are involved in. Earlier research showed that GDF-5 and C-1-1 played a key role in the regulation of cartilage development and maintenance of chondrocytes' permanent phenotype. Epigenetics is the bridge across the environmental factors and genes. The aberrant epigenetic modification of GDF-5/Smad/C-1-1 pathway is closely related to bone and joint diseases' occurrence and development, but there are no studies confirmed . In this study with immunoprecipitation and chip technology we will investigate the activity of GDF-5/Smad/C-1-1 signaling pathway in different pathological stages and the key factors which have the gene methylation and histone acetylation changes in the osteoarthritis model and clear whether the change will result in the inhibition of GDF-5/Smad/C-1-1 pathway, which then results in articular cartilage degeneration. By using specific intervention means, aberrant epigenetic modifications of the GDF-5/Smad/C-1-1 pathway are changed with an aim to relieve or cure OA. Then we will explore the effect of epigenetic modification by which the GDF-5/Smad/C-1-1 signaling pathway is inhibited in the pathogenesis of OA, which will provide new sights into clinical early diagnosis and treatment of OA.