Prostaglandin E₂ and its cognate EP receptors control human adult articular cartilage homeostasis and are linked to the pathophysiology of osteoarthritis

Abstract

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 realtime 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 painassociated 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.

A Three-Dimensional Chondrocyte-Macrophage Coculture System to Probe Inflammation in Experimental Osteoarthritis

“…2A), both of which are associated with OA inflammation. 65,66 At the protein level, however, only the increase in IL-6 (*366-fold; p = 0.002) expression was statistically significant (Fig. 2C).…”

Estrogen receptor–related receptor α regulation by interleukin‐1β in prostaglandin E2– and cAMP‐dependent pathways in osteoarthritic chondrocytes

“…Although 4 different PGE 2 receptors (EPs 1-4) have been identified, human chondrocytes express primarily the EP2 and EP4 isoforms. Which of these plays a predominant role in OA is still a subject of controversy (33,34), but both activate the cAMP/PKA pathway (35), stimulating a vicious circle in which PGE 2 regulates the expression of cytokines, including IL-1␤ and IL-6 (3,36).…”

Immune Modulation to Improve Tissue Engineering Outcomes for Cartilage Repair in the Osteoarthritic Joint

“…51,52 Synovial macrophages have been identified as key players mediating osteophyte formation in OA, with a significant reduction in TGF-b-induced osteophyte formation observed following the depletion of synovial macrophages utilizing clondronate liposomes. 53,54 Wang et al 45 Li et al 12 Johnson et al…”

“…7 Additionally, proinflammatory mediators detected in synovial fluid of OA joints are known to stimulate degradation of cartilage and inhibit matrix synthesis. [8][9][10][11][12][13] Inflammation of the synovial membrane may be a primary occurrence in disease pathogenesis, with thickening of the synovial membrane identified by MRI in patients with early stage and mild OA.…”