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

Abstract

OBJECTIVES:

To investigate the relative contribution of the cyclooxygenase (COX) isoenzymes COX-1 and COX-2 to prostaglandin E2 (PGE2) 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 PGE2 release from inflamed synovial tissue (0.1-10 microM, 3 and 6 h incubation time) were compared. Release of PGE2 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 microM) and decreased (0.1-1 microM), respectively, during 6 h: At 10 microM, 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 microM, 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 PGE2.

CONCLUSIONS:

With respect to the concentrations studied, the data suggest that in inflamed synovial tissue in OA, up to 30% of PGE2 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.

• Authors: Holger Knorth, Peter Dorfmüller, Rainer Lebert, Wolfgang E Schmidt, Ralf H Wittenberg, Matthias Heukamp, Matthias Wiese, Roland E Willburger
• Journal: Osteoarthritis and cartilage (Osteoarthritis Cartilage) Vol. 12 Issue 8 Pg. 658-66 (Aug 2004) ISSN: 1063-4584 [Print] England
• PMID: 15262246 (Publication Type: Journal Article)

Chemical References

• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors
• Isoenzymes
• Membrane Proteins
• Cyclooxygenase 1
• Cyclooxygenase 2
• PTGS1 protein, human
• PTGS2 protein, human
• Prostaglandin-Endoperoxide Synthases
• Dinoprostone

Topics

• Aged
• Culture Techniques
• Cyclooxygenase 1
• Cyclooxygenase 2
• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors (pharmacology)
• Dinoprostone (metabolism)
• Dose-Response Relationship, Drug
• Female
• Humans
• Isoenzymes (antagonists & inhibitors, metabolism, physiology)
• Male
• Membrane Proteins
• Middle Aged
• Osteoarthritis, Knee (enzymology, metabolism, pathology)
• Prostaglandin-Endoperoxide Synthases (metabolism, physiology)
• Severity of Illness Index
• Synovial Membrane (drug effects, enzymology)
• Synovitis (enzymology, metabolism, pathology)