Cyclooxygenase 2-dependent prostaglandin E2 modulates cartilage proteoglycan degradation in human osteoarthritis explants.
OBJECTIVE
To examine cyclooxygenase-2 (COX-2) enzyme expression, its regulation by interleukin-1 beta (IL-1 beta), and the role of prostaglandin E(2) (PGE(2)) in proteoglycan degradation in human osteoarthritic (OA) cartilage.


METHODS
Samples of human OA articular cartilage, meniscus, synovial membrane, and osteophytic fibrocartilage were obtained at knee arthroplasty and cultured ex vivo with or without IL-1 beta and COX inhibitors. COX expression was evaluated by immunohistochemistry and Western blot analysis. The enzymatic activity of COX was measured by conversion of arachidonic acid to PGE(2). Cartilage degradation was evaluated by measuring the accumulation of sulfated glycosaminoglycans in the medium.


RESULTS
IL-1 beta induced robust expression of COX-2 and PGE(2) in OA meniscus, synovial membrane, and osteophytic fibrocartilage explants, whereas low levels were produced in OA articular cartilage. IL-1 beta also induced cartilage proteoglycan degradation in OA synovial membrane-cartilage cocultures. Increased proteoglycan degradation corresponded to the induction of COX-2 protein expression in, and PGE(2) production from, the synovial membrane. Dexamethasone, neutralizing IL-1 beta antibody, or the selective COX-2 inhibitor, SC-236, attenuated both the IL-1 beta-induced PGE(2) production and cartilage proteoglycan degradation in these cocultures. The addition of PGE(2) reversed the inhibition of proteoglycan degradation caused by SC-236.


CONCLUSIONS
IL-1 beta-induced production of COX-2 protein and PGE(2) was low in OA articular cartilage compared with that in the other OA tissues examined. IL-1 beta-mediated degradation of cartilage proteoglycans in OA synovial membrane-cartilage cocultures was blocked by the selective COX-2 inhibitor, SC-236, and the effect of SC-236 was reversed by the addition of exogenous PGE(2). Our data suggest that induction of synovial COX-2-produced PGE(2) is one mechanism by which IL-1 beta modulates cartilage proteoglycan degradation in OA.
Arthritis and Inflammation Pharmaclogy, Pharmacia Corporation, St. Louis, Missouri 63017, USA. medora.m.hardy@pharmacia.com
Medora M
MM
Hardy
Karen
K
Seibert
Pamela T
PT
Manning
Mark G
MG
Currie
B Mark
BM
Woerner
Dorothy
D
Edwards
Alane
A
Koki
Catherine S
CS
Tripp
D000368:Aged; D000906:Antibodies / Q000494:pharmacology; D002356:Cartilage / Q000378:metabolism*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000502:physiology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000276:immunology / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D008592:Menisci, Tibial / Q000378:metabolism; D010003:Osteoarthritis / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011509:Proteoglycans / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013583:Synovial Membrane / Q000378:metabolism; D000096926:Benzenesulfonamides
D000906:Antibodies; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D003907:Dexamethasone; D015232:Dinoprostone; D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D011509:Proteoglycans; D011720:Pyrazoles; D013449:Sulfonamides; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C496540:PTGS2 protein, human