Induction of cyclooxygenase-2 by mechanical stress through a nitric oxide-regulated pathway

AbstractObjective Biomechanical signals play important roles in regulating the homeostasis of articular cartilage, but under abnormal conditions may be a critical factor in the onset and progression of arthritis. Prostaglandin E2 (PGE2) and nitric oxide (NO), derived from the enzymes cyclo-oxygenase 2 (COX2) and NO synthase 2 (NOS2), are inflammatory mediators that modulate numerous physiological and pathophysiological processes and are potentially important pharmacological targets in osteoarthritis. The goal of this study was to determine the effect of mechanical compression on PGE2 production in the presence of selective NOS2 and COX2 inhibitors.Methods Articular cartilage explants harvested from 2–3-year-old pigs were subjected to intermittent compression at 0.5Hz over a range of stress magnitudes. PGE2 and NO production into the media were determined in the presence and absence of the NOS2 inhibitor 1400W or the COX2 inhibitor NS398. COX2 protein levels were determined by immunoblot analysis.Results Mechanical compression significantly increased NO and PGE2 synthesis in a manner that was dependent on the magnitude of stress. The selective COX2 inhibitor blocked compression-induced NO and PGE2 production. Compression in the presence of 1400W further increased COX2 expression resulting in a 10-fold increase in PGE2 production compared to uncompressed explants with 1400W and a 40-fold increase in PGE2 compared to uncompressed explants without 1400W.Conclusion Mechanical compression of articular cartilage increased COX2 and PGE2 production through a NO-dependent pathway, and therefore pharmacological agents that target the NOS2 pathway in cartilage may have a significant influence on prostanoid production in the joint. Copyright 2002 OsteoArthritis Research Society International. Published by Elsevier Science Ltd. All rights reserved