Prostaglandin E₂ 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 E₂ (PGE₂) and osteoarthritis (OA) by characterizing the catabolic effects of PGE₂ and its unique receptors in human adult articular chondrocytes. Methods. Human adult articular chondrocytes were cultured in monolayer or alginate beads with and without PGE₂ 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 realtime reverse transcription-polymerase chain reaction and Western blotting, respectively, using a monolayer cell culture model. Results. Stimulation of human articular chondrocytes with PGE₂ 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. PGE₂ 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 PGE₂ or an EP2 receptor-specific agonist inhibited activation of Akt that was induced by insulin-like growth factor 1. Conclusion. PGE₂ 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.