Protection of joint destruction through suppression of integrin signaling synovial cells in rheumatoid

虽然胶原酶活性已被证明是这一过程所必需的，但对软骨侵入的过程了解甚少。除了α5和β1整合素亚基外，类风湿滑膜成纤维细胞（RSF）在pannus-软骨连接处新表达α4整合素亚基。本研究旨在探讨α4β1整合素信号在RSF生成基质金属蛋白酶（matrix metalloproteinase， MMP）中的作用。在类风湿性关节炎患者的膝关节置换手术中获得RSF，并在单层中培养。免疫沉淀显示RSF中存在α4整合素亚基。用cooh末端肝素结合纤维连接蛋白片段（HBFN-f）和由HBFN-f衍生的可结合α4β1整合素的合成肽CS-1处理后，RSF分泌的MMP-1、MMP-3和MMP-13呈剂量依赖性增加，而用对照肽或不含肽孵育的RSF分泌的这些MMPs几乎无法检测到。抗α4整合素抗体阻断HBFN-f的作用。特异性MAP激酶抑制剂的抑制研究表明，通过α4β1整合素产生MMP涉及ERK、p38和JNK。α4β1整合素与配体的连接导致RSF大量产生胶原酶（MMP-1和MMP-13）和基质溶解素1 （MMP-3）。因此，α4β1整合素刺激pannus-软骨交界处的RSF可能导致pannus通过MMP诱导破坏软骨。MAP激酶抑制可能有效抑制α4β1整合素信号通路。

The process of cartilage invasion by pannus is poorly understood, although collagenase activity has been shown to be required for the process. Besides α5 and β1 integrin subunits, rheumatoid synovial fibroblasts (RSF) neoexpress α4 integrin subunit at the pannus-cartilage junction. The purpose of this study was to investigate the role of α4β1 integrin signaling in matrix metalloproteinase (MMP) production by RSF. RSF were obtained from knee joints at replacement surgery for patients with rheumatoid arthritis, and cultured in monolayer. Immunoprecipitation revealed the presence of α4 integrin subunit in cultured RSF. Treatment with COOH-terminal heparin-binding fibronectin fragment (HBFN-f) and the synthetic peptide CS-1 derived from HBFN-f both of which can bind α4β1 integrin, resulted in enhanced secretion of MMP-1, MMP-3, and MMP-13 from RSF in a dose-dependent manner, while RSF incubated with control peptide or without peptides secreted barely detectable levels of those MMPs. Anti-α4 integrin antibody blocked the action of HBFN-f. Inhibition studies with specific MAP kinase inhibitors revealed that MMP production through α4β1 integrin involved ERK, p38, and JNK.Ligation of α4β1 integrin with the ligand caused significant production of collagenases (MMP-1 and MMP-13) and stromelysin 1 (MMP-3) by RSF. Thus, stimulation of α4β1 integrin on RSF at the pannus-cartilage junction may contribute to cartilage destruction by pannus through MMP induction. MAP kinase inhibition may be effective for suppression of α4β1 integrin signaling.