Functional genomic analysis in arthritis-affected cartilage:: Yin-yang regulation of inflammatory mediators by α5β1 and αvβ3 integrins
Functional genomic analysis in arthritis-affected cartilage:: Yin-yang regulation of inflammatory mediators by α5β1 and αvβ3 integrins
复制标题
DOI：
10.4049/jimmunol.164.5.2684
复制
发表时间：
2000-03-01
影响因子：
4.4
通讯作者：
Amin, AR
中科院分区：
文献类型：
--
作者：
Attur, MG;Dave, MN;Amin, AR
骨关节炎影响的软骨表现出纤维连接蛋白(FN)和骨桥蛋白(OPN)mRNA的表达增强。在差异显示和生物信息学屏幕上。功能基因组分析表明，FN和OPN的整合素受体α(5)β(1)和α(V)β(3)的结合对软骨细胞的功能有深远的影响。通过激活M4B JBS5(其作用类似于FN N末端片段的激动剂)连接α(5)β(1)，上调炎症介质如NO和PGE(2)以及细胞因子IL-6和IL-8。此外，α(5)β(1)整合素连接上调这些促炎介质是通过诱导和自分泌产生IL-1β介导的，因为II型可溶性IL-1诱骗受体抑制了它们的产生。相反，α(V)β(3)复合体特异性功能阻断单抗(LM609)作为一种类似于OPN的激动剂，通过骨关节炎影响的软骨和激活的牛软骨细胞以显性负向方式减弱IL-1β、NO和PGE(2)的产生(由α(5)β(1)、IL-1β、IL-18或IL-1β、TNF-α和LPS触发)。这些数据显示了整合素之间的信号机制的相互作用，并表明整合素介导的“外向内”和“内向外”信号很可能影响软骨的动态平衡，其调控的解除可能在骨关节炎的发病机制中发挥作用。
Osteoarthritis-affected cartilage exhibits enhanced expression of fibronectin (FN) and osteopontin (OPN) mRNA. in differential display and bioinformatics screen. Functional genomic analysis shows that the engagement of the integrin receptors alpha(5)beta(1) and alpha(v)beta(3) of FN and OPN, respectively, have profound effects on chondrocyte functions. Ligation of alpha(5)beta(1) using activating m4b JBS5 (which acts as agonist similar to FN N-terminal fragment) up-regulates the inflammatory mediators such as NO and PGE(2) as well as the cytokines, IL-6 and IL-8. Furthermore, up-regulation of these proinflammatory mediators by alpha(5)beta(1) integrin ligation is mediated via induction and autocrine production of IL-1 beta, because type II soluble IL-1 decoy receptor inhibits their production. In contrast, alpha(v)beta(3) complex-specific function-blocking mAb (LM609), which acts as an agonist similar to OPN, attenuates the production of IL-1 beta, NO, and PGE(2) (triggered by alpha(5)beta(1), IL-1 beta, IL-18, or IL-1 beta, TNF-alpha, plus LPS) in a dominant negative fashion by osteoarthritis-affected cartilage and activated bovine chondrocytes. These data demonstrate a cross-talk in signaling mechanisms among integrins and show that integrin-mediated "outside in" and "inside out" signaling very likely influences cartilage homeostasis, and its deregulation may play a role in the pathogenesis of osteoarthritis.