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

通过抑制类风湿病中整合素信号传导滑膜细胞来保护关节破坏

基本信息

批准号：
14571375
负责人：
YASUDA Tadashi
金额：
$ 2.11万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571375/
关键词：
synovial cells integrin rheumatoid arthritis MMP fibronectin fragment MAP kinase joint destruction pannus フィブロネクチンフラグメント

项目摘要

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.

尽管已证明胶原酶活性是该过程所必需的，但对Pannus的软骨侵袭过程的理解很少。除α5和β1整合素亚基外，类风湿滑膜成纤维细胞（RSF）NEOExpressα4整合蛋白亚基处的Pannus-Cartilage Junction。这项研究的目的是研究α4β1整合素信号传导在RSF生产基质金属蛋白酶（MMP）中的作用。 RSF是从膝关节替换手术中获得类风湿关节炎患者的膝关节，并在单层中培养。免疫沉淀显示培养的RSF中存在α4整合素亚基。 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 petides secreted barely这些MMP的可检测水平。抗α4整合素抗体阻止了HBFN-F的作用。对特定MAP激酶抑制剂的抑制研究表明，通过α4β1整合蛋白通过ERK，p38和JNK的MMP产生。与配体的α4β1整合素的结合ligation ligand ligand ligand ligand ligand ligand ligand conte contecranse（MMP-1和MMP-13）和曲粒蛋白1（MMP-3）导致大量产生胶原酶（MMP-1和MMP-13）（MMP-3）。那就是在Pannus-Cartilage结处对RSF上α4β1整合素的刺激可能导致Pannus通过MMP诱导造成软骨破坏。 MAP激酶抑制可能有效抑制α4β1整合素信号传导。