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

Xin Li, Michael Ellman, Prasuna Muddasani, James H.C. Wang, Gabriella Cs-Szabo, Andre J. Van Wijnen, Hee Jeong Im

Research output: Contribution to journalArticle

103 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)513-523
Number of pages11
JournalArthritis and rheumatism
Volume60
Issue number2
DOIs
StatePublished - Feb 2009

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

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