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)
|