| 19180509 |
Li X, Ellman M, Muddasani P, Wang JH, Cs-Szabo G, van Wijnen AJ, Im HJ: Prostaglandin E2 and its cognate EP receptors control human adult articular cartilage homeostasis and are linked to the pathophysiology of osteoarthritis. Arthritis Rheum. 2009 Feb;60(2):513-23.
OBJECTIVE: To elucidate the pathophysiologic links between prostaglandin E (2) (PGE (2)) and osteoarthritis (OA) by characterizing the catabolic effects of PGE (2) and its unique receptors in human adult articular chondrocytes. METHODS: Human adult articular chondrocytes were cultured in monolayer or alginate beads with and without PGE (2) and/or agonists of EP receptors, antagonists of EP receptors, and cytokines. Cell survival, proliferation, and total proteoglycan synthesis and accumulation were measured in alginate beads. Chondrocyte-related gene expression and phosphatidylinositol 3-kinase/Akt signaling were assessed by real-time reverse transcription-polymerase chain reaction and Western blotting, respectively, using a monolayer cell culture model. RESULTS: Stimulation of human articular chondrocytes with PGE (2) through the EP2 receptor suppressed proteoglycan accumulation and synthesis, suppressed aggrecan gene expression, did not appreciably affect expression of matrix-degrading enzymes, and decreased the type II collagen:type I collagen ratio. EP2 and EP4 receptors were expressed at higher levels in knee cartilage than in ankle cartilage and in a grade-dependent manner. PGE (2) titration combined with interleukin-1 (IL-1) synergistically accelerated expression of pain-associated molecules such as inducible nitric oxide synthase and IL-6. Finally, stimulation with exogenous PGE (2) or an EP2 receptor-specific agonist inhibited activation of Akt that was induced by insulin-like growth factor 1. CONCLUSION: PGE (2) exerts an antianabolic effect on human adult articular cartilage in vitro, and EP2 and EP4 receptor antagonists may represent effective therapeutic agents for the treatment of OA. |
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