Superinduction of cyclooxygenase-2 activity in human osteoarthritis-affected cartilage - Influence of nitric oxide

Cartilage specimens from osteoarthritis (OA)-affected patients spontaneously released PGE(2) at 48 h in ex vivo culture at levels at least 50-fold higher than in normal cartilage and 18-fold higher than in normal cartilage + cytokines + endotoxin. The superinduction of PGE(2) production coincides with the upregulation of cyclooxygenase-2 (COX-2) in OA-affected cartilage. Production of both nitric oxide (NO) and PGE(2) by OA cartilage explants is regulated at the level of transcription and translation. Dexamethasone inhibited only the spontaneously released PGE(2) production, and not NO, in OA-affected cartilage. The NO synthase inhibitor HNG-monomethyl-L-arginine monoacetate inhibited OA cartiIage NO production by > 90%, but augmented significantly (twofold) the spontaneous production of PGE(2) in the same explants. Similarly, addition of exogenous NO donors to OA cartilage significantly inhibited PGE(2) production. Cytokine + endotoxin stimulation of OA explants increased PGE(2) production above the spontaneous release. Addition of L-NMMA further augmented cytokine-induced PGE(2) production by at least fourfold. Inhibition of PGE(2) by COX-2 inhibitors (dexamethasone or indomethacin) or addition of exogenous PGE(2) did not significantly affect the spontaneous NO production. These data indicate that human OA-affected cartilage in ex vivo conditions shows (a) superinduction of PGE(2) due to upregulation of COX-2, and (b) spontaneous release of NO that acts as an autacoid to attenuate the production of the COX-2 products such as PGE(2). These studies, together with others, also suggest that PGE(2) may be differentially regulated in normal and OA-affected chondrocytes.