Participation of cyclooxygenase-1 in prostaglandin E2 release from synovitis tissue in primary osteoarthritis in vitro

Objectives: To investigate the relative contribution of the cyclooxygenase (COX) isoenzymes COX-1 and COX-2 to prostaglandin E-2 (PGE(2)) release from inflamed synovial tissue in N = 10 patients with primary osteoarthritis (OA) in vitro and to determine possible effects of COX inhibitors on the gene expression of synovial COX-1 and COX-2. Design: The effects of a COX-unspecific nonsteroidal anti-inflammatory drug (NSAID; diclofenac), a selective COX-1 inhibitor (SC-560) and a selective COX-2 inhibitor (SC-58125) on PGE(2) release from inflamed synovial tissue (0.1-10 muM, 3 and 6h incubation time) were compared. Release of PGE(2) into the incubation media was measured by means of the enzyme-linked immunosorbent assay. Expression of synovial COX-1/-2 was quantified by means of real-time reverse transcriptase polymerase chain reaction (RT-PCR). Results: All agents inhibited synovial PGE2 release dose-dependently. Compared to short-term incubations, the inhibitory potency of diclofenac, SC-58125 and SC-560 was increased (0.1-10 muM) and decreased (0.1-1 muM), respectively, during 6 h: At 10 muM, SC-560 and SC-58125 had obviously lost their specificity for COX-1 and COX-2, respectively, indicated by a comparable inhibitory potency of the selective COX-1 inhibitor (86.6%) and the selective COX-2 inhibitor (96.6%) within identical tissue specimens. In contrast, at 1 muM, 83% and 62.8% inhibition was seen for diclofenac and SC-58125, respectively. SC-560 showed 30.6% inhibition (P<0.05). In contrast to synovial COX-1, RT-PCR revealed a significant induction of COX-2 through PGE(2). Conclusions: With respect to the concentrations studied, the data suggest that in inflamed synovial tissue in OA, up to 30% of PGE(2) might be generated via the COX-1 pathway. In therapy of OA, the relative contribution of COX-1 in synovial inflammation should be considered, weighing the potency of COX-unspecific NSAID against the assumed superior gastrointestinal safety profile of selective COX-2 inhibitors. (C) 2004 OsteoArthritis Research Society International. Published by Elsevier Ltd. All rights reserved.