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 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 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 alpha 5 beta1 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 PGE2 (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.
Attur
M G
MG
Department of Rheumatology, Hospital for Joint Diseases, New York, NY 10003, USA.
Dave
M N
MN
Clancy
R M
RM
Patel
I R
IR
Abramson
S B
SB
Amin
A R
AR
D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002358:Cartilage, Articular / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002417:Cattle; D019902:Chondrocytes / Q000378:metabolism; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D020382:Interleukin-18 / Q000502:physiology; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D008024:Ligands; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008875:Middle Aged; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D010003:Osteoarthritis / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017469:Receptors, Fibronectin / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D019030:Receptors, Vitronectin / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D015854:Up-Regulation / Q000276:immunology
D000911:Antibodies, Monoclonal; D018836:Inflammation Mediators; D007375:Interleukin-1; D020382:Interleukin-18; D015850:Interleukin-6; D016209:Interleukin-8; D008024:Ligands; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D017469:Receptors, Fibronectin; D019030:Receptors, Vitronectin; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D015232:Dinoprostone