csrp2在类风湿性关节炎滑膜增殖侵袭中的作用研究

Abnormal proliferation and invasion of synovial tissue is important pathological changes in the process of rheumatoid arthritis (RA). Abundant evidence showed that RA synovial fibroblasts (FLSs) which had the transformed characteristic played the role of "active participant" in the process of pathological changes in RA synovial. csrp2 was the high expression of differentially genes in RA FLSs by cDNA microarray screening. Further studies showed that: 1) csrp2 was universal high expression in RA synovial tissue; 2) Down-regulation of csrp2 significantly inhibited cell proliferation and invasion capacity in RA FLSs; 3) Local down-regulation of csrp2 improved synovial hyperplasia and bone damage in knee of CIA rats. Although literatures reported mouse embryonic fibroblasts csrp2 negative regulate the combination Runx1 and tumor suppressor gene p21cip1 promoter to inhibit transcription of p21.The role and mechanism of csrp2 in process of proliferation and invasion in RA FLSs were not reported. This study will base on the previous work and further explore the molecular mechanism of csrp2 promoting RA synovial hyperplasia and invasion from the cellular level and the animal level. The study will provide new strategies for the prevention and treatment of RA.

滑膜组织异常增殖侵袭是类风湿性关节炎（RA）病程中重要的病理改变。大量证据显示具有转化细胞特征的RA滑膜成纤维细胞（FLSs）在RA滑膜病理改变进程中扮演了"主动参与者"的角色。csrp2是我们利用基因表达谱芯片筛选到的在RA FLSs中高表达的差异基因。进一步研究发现1）csrp2在RA滑膜组织中高表达具有普遍性；2）RA FLSs中下调csrp2可显著抑制细胞的增殖和侵袭能力；3）CIA大鼠膝关节局部下调csrp2对滑膜增生和骨破坏有明显改善作用。虽有文献报道小鼠胚胎纤维母细胞中csrp2可通过负性调控Runx1与抑癌基因p21cip1启动子的结合而抑制p21转录，但有关csrp2在RA FLSs增殖侵袭过程中的作用及机制尚无报道。本研究拟在前期工作的基础上，从细胞水平和动物水平，探索csrp2促进RA滑膜增生侵袭的分子机制，为RA的防治提供新策略。

类风湿性关节炎是一种以关节病变为主要特征的慢性自身免疫性疾病。滑膜组织异常增殖侵袭、过度分泌基质金属蛋白酶（MMPs）进而破坏关节软骨及软骨下骨是类风湿性关节炎（RA）病程中重要的病理改变之一。研究显示具有转化细胞特征的成纤维样滑膜细胞（FLSs）在RA滑膜病理改变中发挥了重要作用。我们利用表达谱芯片筛选获得了RA FLSs中高表达的差异基因csrp2，其表达产物为具有接头蛋白活性的CRP2蛋白。进一步扩大临床样本后发现csrp2在RA滑膜组织中的表达水平显著高于正常滑膜组织，这种高表达与MMP9的表达水平具有一致性，这提示csrp2具有重要的临床价值。细胞水平下调csrp2能够抑制MMP9表达进而削弱RA FLSs的侵袭能力。为了深入探索csrp2调控MMP9的详细机制，我们以寻找接头蛋白CRP2的相互作用分子为突破口，免疫沉淀结合质谱分析，获得了CRP2互作蛋白RUNX2，Csrp2对MMP9表达的正性调控作用正是通过其结合转录因子Runx2，进而提高Runx2与MMP9启动子的结合活性来实现。在体实验显示，下调CIA大鼠膝关节局部滑膜组织中csrp2的表达，对滑膜增生和骨破坏有明显改善作用。我们的工作首次证实CRP2与RUNX2相互作用促进MMP9表达和分泌，在RA滑膜组织恶性侵袭中的作用，为RA的防治提供了新的靶点。上述工作开展过程中，培养青年医师2人，发表SCI文章2篇，另有题为CRP2 is a novel regulatory factor of FLSs in RA synovial invasion via upregulating MMP9 with RUNX2的文章，投至J RHEUMATOL杂志，目前处于under view阶段。