Prostaglandin E 2 and its cognate EP receptors control human adult articular cartilage homeostasis and are linked to the pathophysiology of osteoarthritis

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.