从损伤相关分子模式激活NLRP3炎症小体角度探讨尿酸参与骨关节炎细胞外基质降解的机制

Osteoarthritis (OA) is the common disabling degenerative joint disease. Extracellular matrix degradation is a key event in the pathogenesis. Uric acid is an independent risk factor for osteoarthritis, of which the role needs to be deeply studyed. We have observed that the mean uric acid concentrations in osteoarthritic synovial fluid were significantly higher than that in their paired serum. The uric acid concentrations were strongly correlated with the concentrations of IL-1β, IL-18, matrix metalloproteinases (MMPs) in osteoarthritic synovial fluid. Moreover, Synovial fluid uric acid was also strongly and positively associated with OA severity as measured by radiograph. With the methods of gene silence，mouse models of OA and gene knock-out technology, we will further study the following aspects. (1) Uric acid directly induces the expressions of IL-1β, IL-18, and MMPs in vivo and in vitro. (2) Two requirements for NLRP3 inflammasome activation were provided by uric acid via NFκB pathway and Nek7. We try to reveal the possible molecular mechanism of uric acid in osteoarthritic extracellular matrix degradation by regulating MMPs via the NLRP3 inflammasome-dependent damage-associated molecular pattern. We hope the outcomes will provide experimental basis and new ideas for the treatment of OA.

骨关节炎（Osteoarthritis，OA）是一种常见的致残性关节疾病，细胞外基质降解是发病的核心环节。尿酸被认为是OA的危险信号，其在发病中可能起关键作用。我们前期发现：OA患者关节液尿酸水平升高，其水平与IL-1β、IL-18、基质金属蛋白酶（Matrix metalloproteinases, MMPs）的表达，以及与OA严重程度成正相关。本研究采用基因沉默、OA动物模型、基因敲除鼠等研究方法，拟通过体内外实验：验证尿酸能调控IL-1β、IL-18、MMPs的表达，影响OA细胞外基质降解；证实尿酸通过NFκB、Nek7等关键因子，作为第一信号、第二信号充分激活NLRP3炎症小体是其作用的信号通路。最终，揭示尿酸通过损伤相关分子模式激活NLRP3炎症小体，调控IL-1β、IL-18的表达，最终通过MMPs参与到OA细胞外基质降解中。该研究将为OA的治疗提供实验依据和新的思路。