PGE2 signaling through the EP4 receptor on fibroblasts upregulates RANKL and stimulates osteolysis

Ryosuke Tsutsumi, Chao Xie, Xiaochao Wei, Minjie Zhang, Xinping Zhang, Lisa M. Flick, Edward M. Schwarz, Regis J. O'Keefe

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Periprosthetic osteolysis is the most common cause of aseptic loosening in total joint arthroplasty. The role of inflammatory mediators such as prostaglandin E2 (PGE2) and osteoclast promoting factors including RANKL in the pathogenesis of osteolysis has been well characterized. However, the PGE2 receptor (EP1, EP2, or EP4), and cell type in which it is expressed, which is responsible for PGE2 induction of RANKL during wear debris-induced osteolysis, has yet to be elucidated. To address this, we used mice genetically deficient in these EP receptors to assess PGE2 and wear debris responses in vitro and in vivo. Wear debris-induced osteolysis and RANKL expression were observed at similar levels in WT, EP1-/-, and EP2-/- mice, indicating that these receptors do not mediate PGE2 signals in this process. A conditional knockout approach was used to eliminate EP4 expression in FSP1+ fibroblasts that are the predominant source of RANKL. In the absence of EP4, fibroblasts do not express RANKL after stimulation with particles or PGE2, nor do they exhibit high levels of osteoclasts and osteolysis. These results show that periprosthetic fibroblasts are important mediators of osteolysis through the expression of RANKL, which is induced after PGE2 signaling through the EP4 receptor.

Original languageEnglish
Pages (from-to)1753-1762
Number of pages10
JournalJournal of Bone and Mineral Research
Volume24
Issue number10
DOIs
StatePublished - Oct 1 2009
Externally publishedYes

Keywords

  • EP4
  • Fibroblast
  • Inflammatory bone loss
  • Prostaglandin
  • RANKL

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