SUPERINDUCTION OF CYCLOOXYGENASE-2 ACTIVITY IN HUMAN OSTEOARTHRITIS-AFFECTED CARTILAGE - INFLUENCE OF NITRIC-OXIDE

Cartilage specimens from osteoarthritis (OA)-affected patients spontan eously released PGE(2) at 48 h in ex vivo culture at levels at least 5 0-fold higher than in normal cartilage and 18-fold higher than in norm al cartilage + cytokines + endotoxin. The superinduction of PGE(2) pro duction 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 releas ed PGE(2) production, and not NO, in OA-affected cartilage. The NO syn thase inhibitor HNG-monomethyl-L-arginine monoacetate inhibited OA car tiIage NO production by > 90%, but augmented significantly (twofold) t he spontaneous production of PGE(2) in the same explants. Similarly, a ddition of exogenous NO donors to OA cartilage significantly inhibited PGE(2) production. Cytokine + endotoxin stimulation of OA explants in creased 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 af fect the spontaneous NO production. These data indicate that human OA- affected cartilage in ex vivo conditions shows (a) superinduction of P GE(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 prod ucts such as PGE(2). These studies, together with others, also suggest that PGE(2) may be differentially regulated in normal and OA-affected chondrocytes.