Functional genomic analysis in arthritis-affected cartilage: Yin-yang regulation of inflammatory mediators by alpha(5)beta(1) and alpha(v)beta(3) integrins

Osteoarthritis-affected cartilage exhibits enhanced expression of fibronect in (FN) and osteopontin (OPN) mRNA. in differential display and bioinformat ics screen. Functional genomic analysis shows that the engagement of the in tegrin receptors alpha(5)beta(1) and alpha(v)beta(3) of FN and OPN, respect ively, have profound effects on chondrocyte functions. Ligation of alpha(5) beta(1) using activating m4b JBS5 (which acts as agonist similar to FN N-te rminal 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 med iated 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 a gonist 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 carti lage and activated bovine chondrocytes. These data demonstrate a cross-talk in signaling mechanisms among integrins and show that integrin-mediated "o utside in" and "inside out" signaling very likely influences cartilage home ostasis, and its deregulation may play a role in the pathogenesis of osteoa rthritis.