SIRT1下调TIMP1在RA晚期关节骨损伤中的作用及分子机制研究

Rheumatoid arthritis (RA) is a disabling joint disease of rheumatism.Unexplained abnormal synovial hyperplasia associated with a large number of pannus formation of the Parcel articular cartilage resulted in that the articular cartilage unable to take the nutrition from the synovial fluid,in turn,caused cartilage degradation,bone destruction,and an increasing in the rheumatoid joint disability.We found that SIRT1 gene was significantly up-regulated expression in the articular bone injury in patients with rheumatoid synovial tissue using the gene chip screening.This result was confirmed by qPCR and Western-blot.We also found that SIRT1 can donw regulate the expression of TIMP1 protein in cultured synovial fibroblast cells,an in vitro RA cell model.TIMP1 plays an important role in promoting matrix degradation,cartilage damagement and cell apoptosis.The mechanisms of the regulation of TIMP1 matrix by SIRT1,however,is unclear.In this project,we are planning to study the role of SIRT1 down regulation of TIMP1 and possble regulation mechanisms in rheumatoid synovial fibroblast-like cells of malignant proliferation and the degradation of articular cartilage in vitro and invio.We will provide a new target for studing the treatment of RA.

类风湿关节炎（RA）是一种以致残性关节病变为主的风湿病。不明原因的关节滑膜异常增生伴有大量血管翳形成包裹关节软骨导致后者无法从关节滑液中获取营养而发生软骨降解和骨破坏增多是RA关节致残的主要原因。我们利用基因芯片筛查发现去乙酰化酶1（SIRT1）在发生关节骨损伤的RA患者滑膜组织中表达显著上调，这一结果亦经qPCR和Western-blot方法得到证实。随后在RA离体滑膜成纤维细胞模型中，对和RA晚期关节骨损伤相关的一系列分子检测中发现SIRT1对基质金属蛋白酶抑制因子1（TIMP1）的表达影响最大，后者在促进基质降解、软骨破坏和促进细胞凋亡等方面具有重要作用。然而SIRT1调控TIMP1的机制目前尚不清楚。本项目拟通过体外和体内实验，研究SIRT1抑制TIMP1表达在RA晚期滑膜成纤维样细胞恶性增殖促进关节软骨降解过程中的作用及可能的分子机制，为RA晚期关节损伤的治疗提供新的靶点。