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PGE2 Signaling Through the EP4 Receptor on Fibroblasts Upregulates RANKL and Stimulates Osteolysis
Author(s) -
Tsutsumi Ryosuke,
Xie Chao,
Wei Xiaochao,
Zhang Minjie,
Zhang Xinping,
Flick Lisa M,
Schwarz Edward M,
O'Keefe Regis J
Publication year - 2009
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.090412
Subject(s) - rankl , osteolysis , osteoclast , prostaglandin e2 receptor , receptor , cancer research , chemistry , bone resorption , prostaglandin e2 , nf κb , microbiology and biotechnology , signal transduction , medicine , endocrinology , biology , activator (genetics) , dentistry , agonist
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.