Participation of cyclooxygenase-1 in prostaglandin E 2 release from synovitis tissue in primary osteoarthritis in vitro

• Published in: Osteoarthritis and cartilage Vol. 12; no. 8; pp. 658 - 666
• Main Authors: Knorth, Holger, Dorfmüller, Peter, Lebert, Rainer, Schmidt, Wolfgang E., Wittenberg, Ralf H., Heukamp, Matthias, Wiese, Matthias, Willburger, Roland E.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.08.2004
• Subjects: COX-1; COX-2; Inflammation; Osteoarthritis; Synovitis; AA; Synovitis; RT; TNFα; IL; COX-2; NR; COX-1; NSAID; Inflammation; COX; bp; RA; SE; PG; Osteoarthritis; PCR; ELISA
• ISSN: 1063-4584; 1522-9653
• DOI: 10.1016/j.joca.2004.05.002

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. 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). 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. 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.