RA-FLS通过MTA1参与类风湿关节炎关节破坏的机制研究

Rheumatoid arthritis (RA) is a systemic inflammatory disorder characterized by chronic synovitis and the erosion of joints. It has been found that the fibroblast-like synoviocytes (FLS) of RA has the characteristics of transformation similar to malignant tumor, deregulated inflammatory response and abnormal secretion of matrix metalloproteinases (MMPs), which may possibly play important roles in the pathogenesis of RA. However, the underlying mechanisms remain largely unknown. Metastasis associated protein1 (MTA1) is an important transcriptional regulator which plays an essential role in cancer cell invasion, matastasis, and inflammation-associated pathology. We have previously found that MTA1 could up-regulate the expression of MMP2 in the Sertoli cells of murine. Very recently we also found that the expression of MTA1 and MMPs in RA-FLS was abnormally higher than that in control cells. Interference of MTA1 expression via in vitro treatment significantly decreased the expression of inflammatory cytokines in synoviocytes of RA. These data collectively suggest that MTA1 maybe directly participate in the pathogenesis of RA through modulation of the inflammation. In this context, the current study is designed: 1) to investigate the expression of MTA1 and its relationship with activity of disease, the expression of inflammatory cytokines and MMPs (1,2,3,9) in FLS of RA and collagen induced arthritis (CIA) animal models; 2)and to study the role and molecular mechanism of MTA1 on the invasion and erosion of joints in RA using the MTA1 knockout mice-based CIA model. It should certainly provide delightful clues to reveal the pathogenesis of FLS in RA.

类风湿关节炎(RA)是一种以滑膜炎、关节破坏为特征的高发病率、高致残率疾病，而成纤维样滑膜细胞(FLS)类肿瘤样的转化特性、炎症反应及其分泌的金属基质蛋白酶(MMPs)在关节破坏中发挥重要作用，但其具体机制尚不清楚。肿瘤转移相关蛋白1(MTA1)在肿瘤侵袭和转移、炎症调控中有重要调节作用；本课题组前期工作发现MTA1可间接上调MMP2的表达。我们近期工作显示，RA-FLS中MTA1及MMPs均异常高表达，体外干涉抑制MTA1可显著降低滑膜细胞表达多种炎性因子，提示MTA1可能直接参与RA病理机制。据此本课题拟进一步研究：1.MTA1在RA-FLS与动物模型滑膜的表达及其与病情、MMPs(1,2,3,9)等表达之间的相关关系；2.采用MTA1 knockout小鼠建立胶原诱导的关节炎模型(CIA)模型，研究MTA1参与RA病理发生的分子机制及信号通路，从而深入揭示RA-FLS的致病机理。