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EP1 −/− mice have enhanced osteoblast differentiation and accelerated fracture repair
Author(s) -
Zhang Minjie,
Ho Hsinchiu,
Sheu Tzongjen,
Breyer Matthew D,
Flick Lisa M,
Jonason Jennifer H,
Awad Hani A,
Schwarz Edward M,
O'Keefe Regis J
Publication year - 2011
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 - 10.1002/jbmr.272
Subject(s) - endochondral ossification , prostaglandin e2 receptor , bone healing , osteoblast , bone remodeling , microbiology and biotechnology , medicine , endocrinology , chemistry , cartilage , receptor , signal transduction , biology , anatomy , in vitro , biochemistry , agonist
As a downstream product of cyclooxygenase 2 (COX‐2), prostaglandin E 2 (PGE 2 ) plays a crucial role in the regulation of bone formation. It has four different receptor subtypes (EP1 through EP4), each of which exerts different effects in bone. EP2 and EP4 induce bone formation through the protein kinase A (PKA) pathway, whereas EP3 inhibits bone formation in vitro. However, the effect of EP1 receptor signaling during bone formation remains unclear. Closed, stabilized femoral fractures were created in mice with EP1 receptor loss of function at 10 weeks of age. Healing was evaluated by radiographic imaging, histology, gene expression studies, micro–computed tomographic (µCT), and biomechanical measures. EP1 −/− mouse fractures have increased formation of cartilage, increased fracture callus, and more rapid completion of endochondral ossification. The fractures heal faster and with earlier fracture callus mineralization with an altered expression of genes involved in bone repair and remodeling. Fractures in EP1 −/− mice also had an earlier appearance of tartrate‐resistant acid phosphatase (TRAcP)–positive osteoclasts, accelerated bone remodeling, and an earlier return to normal bone morphometry. EP1 −/− mesenchymal progenitor cells isolated from bone marrow have higher osteoblast differentiation capacity and accelerated bone nodule formation and mineralization in vitro. Loss of the EP1 receptor did not affect EP2 or EP4 signaling, suggesting that EP1 and its downstream signaling targets directly regulate fracture healing. We show that unlike the PGE 2 receptors EP2 and EP4, the EP1 receptor is a negative regulator that acts at multiple stages of the fracture healing process. Inhibition of EP1 signaling is a potential means to enhance fracture healing. © 2011 American Society for Bone and Mineral Research.