Functional genomic analysis in arthritis-affected cartilage:: Yin-yang regulation of inflammatory mediators by α5β1 and αvβ3 integrins

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.