TY - JOUR
T1 - PGE2 signaling through the EP4 receptor on fibroblasts upregulates RANKL and stimulates osteolysis
AU - Tsutsumi, Ryosuke
AU - Xie, Chao
AU - Wei, Xiaochao
AU - Zhang, Minjie
AU - Zhang, Xinping
AU - Flick, Lisa M.
AU - Schwarz, Edward M.
AU - O'Keefe, Regis J.
PY - 2009/10
Y1 - 2009/10
N2 - 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.
AB - 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.
KW - EP4
KW - Fibroblast
KW - Inflammatory bone loss
KW - Prostaglandin
KW - RANKL
UR - http://www.scopus.com/inward/record.url?scp=70349924967&partnerID=8YFLogxK
U2 - 10.1359/jbmr.090412
DO - 10.1359/jbmr.090412
M3 - Article
C2 - 19419302
AN - SCOPUS:70349924967
SN - 0884-0431
VL - 24
SP - 1753
EP - 1762
JO - Journal of Bone and Mineral Research
JF - Journal of Bone and Mineral Research
IS - 10
ER -