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Functional Genomic Analysis in Arthritis-Affected Cartilage: Yin-Yang Regulation of Inflammatory Mediators by ₅ß₁ and _Vß₃ Integrins¹

Mukundan G. Attur^*, Mandar N. Dave^*, Robert M. Clancy^*, Indravadan R. Patel^*, Steven B. Abramson^*, and Ashok R. Amin^2,*,,

^* Department of Rheumatology, Hospital for Joint Diseases, New York, NY 10003; and Departments of Pathology and Medicine, Kaplan Cancer Center, New York University Medical Center, New York, NY 10016

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 ₅ß₁ and _vß₃ of FN and OPN, respectively, have profound effects on chondrocyte functions. Ligation of ₅ß₁ using activating mAb JBS5 (which acts as agonist similar to FN N-terminal fragment) up-regulates the inflammatory mediators such as NO and PGE₂ as well as the cytokines, IL-6 and IL-8. Furthermore, up-regulation of these proinflammatory mediators by ₅ß₁ integrin ligation is mediated via induction and autocrine production of IL-1ß, because type II soluble IL-1 decoy receptor inhibits their production. In contrast, _vß₃ complex-specific function-blocking mAb (LM609), which acts as an agonist similar to OPN, attenuates the production of IL-1ß, NO, and PGE₂ (triggered by ₅ß₁, IL-1ß, IL-18, or IL-1ß, TNF-, 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.

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