NOV蛋白在类风湿关节炎中的异常表达及机制

Rheumatoid arthritis (RA) is a common chronic autoimmune disease with high disability rate, and characterized by sustained inflammation of joints and destruction of bone and articular cartilage. NOV, a member of CCN family, involves in cartilage formation and ossification. However, the role of NOV on pathogenesis of RA is still unknown. Our previous studies found that the content of NOV is obviously high in plasma and synovial fluid of RA patients and decreases after treatment. In this study, we will first confirm whether NOV is secreted by the fibroblast-like synoviocytes (FLS) and study the mechanism of NOV expression regulation. Next, we will establish the FLS cell lines with NOV overexpression and knockdown, and investigate the effects of NOV on cell proliferation, apoptosis, invasion, cytokines and matrix metalloproteinases (MMPs) production of FLS cells. Then we will characterize the role of NOV on the development of collagen-induced arthritis (CIA) and the destruction of joint synovium and cartilage using NOV transgenic mouse. This project will systematically analyze the molecular mechanism of NOV involving in regulation of the pathogenesis of RA and the significance of NOV as a new RA therapeutic target.

类风湿关节炎（RA）是一种常见的慢性自身免疫性疾病，致残率高，表现为关节的持续炎症反应和骨/软骨破坏。NOV是CCN家族蛋白，参与调控软骨形成和骨化过程，但NOV在RA发病中的作用尚不清楚。申请人前期研究发现NOV在RA患者血浆、滑液中的含量明显升高，且经治疗下降。本项目将首先明确在RA中NOV蛋白异常表达分泌及其调控机制；构建NOV蛋白过表达及沉默滑膜成纤维细胞(FLS)，明确NOV蛋白对FLS的增殖、凋亡、趋化侵袭、细胞因子分泌、金属蛋白酶(MMPs)分泌等作用及调控机制，并通过NOV转基因小鼠明确NOV在胶原诱导关节炎(CIA)小鼠发病中的作用及其对关节滑膜和软骨的影响。本研究将较系统阐述NOV参与调控RA发病的分子机制，明确其作为RA治疗新靶点的意义。

类风湿关节炎（RA）以关节滑膜组织持续增生和骨/软骨破坏为主要表现。CCN家族成员NOV蛋白可以参与调控软骨形成和骨化过程，是否参与RA发病未知。结合前期研究我们发现NOV蛋白在RA中存在差异表达，本研究重点探明NOV蛋白是否参与RA发病过程。首先我们明确了RA患者关节滑液中NOV蛋白含量升高；并且这些蛋白来源于RA患者关节滑膜成纤维细胞（FLS）中NOV蛋白的高表达；接下来，我们发现体外给与NOV蛋白刺激可以促进FLS细胞增殖和基质金属蛋白酶MMP1/MMP9的分泌；同时还可以刺激单核细胞向关节局部趋化及分泌炎性因子IL6，从而参与RA关节局部破坏，在RA发生发展过程中起到重要作用，或可作为RA新型治疗靶点。