GDF11通过调控软骨细胞TNF-α/NF-κB/NLRP3炎性信号系统减轻骨关节炎的作用机制研究

骨关节炎是临床常见退变性疾病，与软骨细胞的炎性反应等过程密切相关。在骨关节炎中，TNF-α/TNFR炎性信号系统可激活NF-κB通路并活化NLRP3炎性小体，从而加速软骨细胞老化。生长分化因子GDF11可抑制TNF-α/NF-κB信号通路激活并降低NLRP3表达水平。另外，我们发现GDF11在炎症疾病中具有保护功能，并在退变软骨中表达降低。然而，GDF11是否在骨关节炎中发挥作用尚有待探索。本课题拟构建软骨组织特异性GDF11基因敲除及转基因小鼠，明确GDF11的缺失及过表达对于骨关节炎发生的影响。同时，借助骨关节炎动物模型及体外细胞实验，阐述GDF11对于软骨退变的作用。另外，阐明GDF11对于软骨细胞线粒体功能及NLRP3炎性小体的调节机制，并探索GDF11对TNF-α/TNFR信号系统及下游NF-κB通路的调控模式。此课题可能为进一步探究骨关节炎发生机制及治疗策略提供线索。

Osteoarthritis is a common degenerative disease in clinic, which is closely associated with inflammatory reaction of chondrocyte. TNF-α/TNFR inflammatory signalling system is known to activate NF-κB pathway and NLRP3 inflammasome in osteoarthritis, which accelerates aging of cartilage. GDF11 antagonizes TNF-α/NF-κB signalling pathway and reduces expression level of NLRP3. We found that GDF11 plays a protective role in inflammatory conditions, and exhibits decreased expression level in degenerative cartilage. However, whether GDF11 is invovled in osteoarthritis development still remains to be elucidated. In the present study, we plan to establish cartilage tissue-specific GDF11 knockout and transgenic mice to clarify the role of endogenous GDF11 in development of osteoarthritis. Besides, animal models and cellular experiments will be performed to testify the association between GDF11 and cartilage degeneration. Moreover, we plan to illustrate the effect of GDF11 in mitochondrial function as well as NLRP3 inflammasome activity, and illuminate the regulatory function of GDF11 on TNF-α/TNFR/ NF-κB signalling pathway, through chondrocyte aging. This study might shed light on underlying mechanism as well as therapeutic strategy for osteoarthritis.