Abstract
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 μM, 3 and 6 h 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 PGE 2 release dose-dependently. Compared to short-term incubations, the inhibitory potency of diclofenac, SC-58125 and SC-560 was increased (0.1–10 μM) and decreased (0.1–1 μM), respectively, during 6 h: At 10 μM, 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 μM, 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.
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