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Division of Rheumatology, New York University School of Medicine and New York University Hospital for Joint Diseases, New York, NY 10003
Elevated levels of PGE2 have been reported in synovial fluid and cartilage from patients with osteoarthritis (OA). However, the functions of PGE2 in cartilage metabolism have not previously been studied in detail. To do so, we cultured cartilage explants, obtained from patients undergoing knee replacement surgery for advanced OA, with PGE2 (0.1–10 µM). PGE2 inhibited proteoglycan synthesis in a dose-dependent manner (maximum 25% inhibition (p < 0.01)). PGE2 also induced collagen degradation, in a manner inhibitable by the matrix metalloproteinase (MMP) inhibitor ilomastat. PGE2 inhibited spontaneous MMP-1, but augmented MMP-13 secretion by OA cartilage explant cultures. PCR analysis of OA chondrocytes treated with PGE2 with or without IL-1 revealed that IL-1-induced MMP-13 expression was augmented by PGE2 and significantly inhibited by the cycolooygenase 2 selective inhibitor celecoxib. Conversely, MMP-1 expression was inhibited by PGE2, while celecoxib enhanced both spontaneous and IL-1-induced expression. IL-1 induction of aggrecanase 5 (ADAMTS-5), but not ADAMTS-4, was also enhanced by PGE2 (10 µM) and reversed by celecoxib (2 µM). Quantitative PCR screening of nondiseased and end-stage human knee OA articular cartilage specimens revealed that the PGE2 receptor EP4 was up-regulated in OA cartilage. Moreover, blocking the EP4 receptor (EP4 antagonist, AH23848) mimicked celecoxib by inhibiting MMP-13, ADAMST-5 expression, and proteoglycan degradation. These results suggest that PGE2 inhibits proteoglycan synthesis and stimulates matrix degradation in OA chondrocytes via the EP4 receptor. Targeting EP4, rather than cyclooxygenase 2, could represent a future strategy for OA disease modification.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by Grant R01-AR047206 from the National Institutes of Health Grant (to S.B.A.) and grants from the Joseph C. and Sophia Abeles Foundation, the Falk Family, and the Riley Family Foundation for their generous financial support for this research.
2 Address correspondence and reprint requests to Dr. Steven B. Abramson, Division of Rheumatology, New York University Hospital for Joint Diseases, 301 East 17th Street, New York, NY 10003. E-mail address: stevenb.abramson{at}nyumc.org
3 Abbreviations used in this paper: OA, osteoarthritis; MMP, matrix metalloproteinase; COX-2, cyclooxygenase 2; ECM, extracellular matrix; QPCR, quantitative PCR; mPGES, microsomal prostaglandin E synthase.
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