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

Objective: 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 0.5 Hz over a range of stress magnitudes. PGE₂ and NO production into the media were determined in the presence and absence of the NOS2 inhibitor 140OW 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 140OW further increased COX2 expression resulting in a 10-fold increase in PGE₂, production compared to uncompressed explants with 140OW 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.