title: Prostaglandin E2 exerts catabolic effects in osteoarthritis cartilage: evidence for signaling via the EP4 receptor.
abstract: Elevated levels of PGE(2) have been reported in synovial fluid and cartilage from patients with osteoarthritis (OA). However, the functions of PGE(2) 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 PGE(2) (0.1-10 muM). PGE(2) inhibited proteoglycan synthesis in a dose-dependent manner (maximum 25% inhibition (p < 0.01)). PGE(2) also induced collagen degradation, in a manner inhibitable by the matrix metalloproteinase (MMP) inhibitor ilomastat. PGE(2) inhibited spontaneous MMP-1, but augmented MMP-13 secretion by OA cartilage explant cultures. PCR analysis of OA chondrocytes treated with PGE(2) with or without IL-1 revealed that IL-1-induced MMP-13 expression was augmented by PGE(2) and significantly inhibited by the cycolooygenase 2 selective inhibitor celecoxib. Conversely, MMP-1 expression was inhibited by PGE(2), 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 PGE(2) (10 muM) and reversed by celecoxib (2 muM). Quantitative PCR screening of nondiseased and end-stage human knee OA articular cartilage specimens revealed that the PGE(2) 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 PGE(2) 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.
authors.affiliation: Division of Rheumatology, New York University School of Medicine and New York University Hospital for Joint Diseases, New York, NY 10003, USA.
authors.forename: Mukundan
authors.initials: M
authors.lastname: Attur
authors.forename: Hayf E
authors.initials: HE
authors.lastname: Al-Mussawir
authors.forename: Jyoti
authors.initials: J
authors.lastname: Patel
authors.forename: Alison
authors.initials: A
authors.lastname: Kitay
authors.forename: Mandar
authors.initials: M
authors.lastname: Dave
authors.forename: Glyn
authors.initials: G
authors.lastname: Palmer
authors.forename: Michael H
authors.initials: MH
authors.lastname: Pillinger
authors.forename: Steven B
authors.initials: SB
authors.lastname: Abramson
mesh_terms: D000368:Aged; D002358:Cartilage, Articular / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D002478:Cells, Cultured; D019902:Chondrocytes / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D015232:Dinoprostone / Q000378:metabolism / Q000502:physiology*; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008875:Middle Aged; D010003:Osteoarthritis / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D018078:Receptors, Prostaglandin E / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015398:Signal Transduction / Q000276:immunology*; D046509:Tissue Culture Techniques
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; C545650:PTGER4 protein, human; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D053509:Matrix Metalloproteinase 13; D020781:Matrix Metalloproteinase 1; D015232:Dinoprostone