Prostaglandin E2and its cognate EP receptors control human adult articular cartilage homeostasis and are linked to the pathophysiology of osteoarthritis

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Abstract
Objective: To elucidate the pathophysiologic links between prostaglandin E2(PGE2) and osteoarthritis (OA) by characterizing the catabolic effects of PGE2and its unique receptors in human adult articular chondrocytes.Methods: Human adult articular chondrocytes were cultured in monolayer or alginate beads with and without PGE2and/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 PGE2through 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. PGE2titration 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 PGE2or an EP2 receptor–specific agonist inhibited activation of Akt that was induced by insulin‐like growth factor 1.Conclusion: PGE2exerts 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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