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


METHODS
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.
Knorth
Holger
H
Orthopaedic University Clinic of Bochum, Department of Rheumaorthopaedic Surgery at St Elisabeth Hospital, Bleichstr. 15, D-44787 Bochum, Germany. h.knorth@gmx.net
Dorfmüller
Peter
P
Lebert
Rainer
R
Schmidt
Wolfgang E
WE
Wittenberg
Ralf H
RH
Heukamp
Matthias
M
Wiese
Matthias
M
Willburger
Roland E
RE
D000368:Aged; D046508:Culture Techniques; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism / Q000502:physiology*; D012720:Severity of Illness Index; D013583:Synovial Membrane / Q000187:drug effects / Q000201:enzymology; D013585:Synovitis / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone