Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Animals
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Antibodies, Monoclonal / pharmacology
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Cartilage, Articular / immunology*
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Cartilage, Articular / metabolism
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Cartilage, Articular / pathology
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Cattle
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Chondrocytes / metabolism
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Dinoprostone / antagonists & inhibitors
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Dinoprostone / biosynthesis
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Humans
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Inflammation Mediators / metabolism*
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Interleukin-1 / antagonists & inhibitors
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Interleukin-1 / biosynthesis
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Interleukin-1 / genetics
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Interleukin-18 / physiology
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Interleukin-6 / biosynthesis
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Interleukin-8 / biosynthesis
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Ligands
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Lipopolysaccharides / antagonists & inhibitors
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Lipopolysaccharides / pharmacology
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Middle Aged
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Nitric Oxide / antagonists & inhibitors
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Nitric Oxide / biosynthesis
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Osteoarthritis / genetics*
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Osteoarthritis / immunology*
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Osteoarthritis / metabolism
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RNA, Messenger / metabolism
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Receptors, Fibronectin / antagonists & inhibitors
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Receptors, Fibronectin / immunology
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Receptors, Fibronectin / metabolism
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Receptors, Fibronectin / physiology*
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Receptors, Vitronectin / immunology
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Receptors, Vitronectin / metabolism
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Receptors, Vitronectin / physiology*
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Signal Transduction / immunology
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Up-Regulation / immunology
Substances
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Antibodies, Monoclonal
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Inflammation Mediators
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Interleukin-1
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Interleukin-18
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Interleukin-6
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Interleukin-8
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Ligands
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Lipopolysaccharides
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RNA, Messenger
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Receptors, Fibronectin
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Receptors, Vitronectin
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Tumor Necrosis Factor-alpha
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Nitric Oxide
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Dinoprostone