EP1-/- mice have enhanced osteoblast differentiation and accelerated fracture repair

Minjie Zhang, Hsin Chiu Ho, Tzong Jen Sheu, Matthew D. Breyer, Lisa M. Flick, Jennifer H. Jonason, Hani A. Awad, Edward M. Schwarz, Regis J. O'Keefe

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

As a downstream product of cyclooxygenase 2 (COX-2), prostaglandin E 2 (PGE2) 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 PGE2 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.

Original languageEnglish
Pages (from-to)792-802
Number of pages11
JournalJournal of Bone and Mineral Research
Volume26
Issue number4
DOIs
StatePublished - Apr 1 2011
Externally publishedYes

Keywords

  • EP1
  • PGE
  • chondrocyte
  • chondrocyte maturation
  • fracture healing
  • mineralization
  • osteoblasts
  • osteoclasts

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    Zhang, M., Ho, H. C., Sheu, T. J., Breyer, M. D., Flick, L. M., Jonason, J. H., Awad, H. A., Schwarz, E. M., & O'Keefe, R. J. (2011). EP1-/- mice have enhanced osteoblast differentiation and accelerated fracture repair. Journal of Bone and Mineral Research, 26(4), 792-802. https://doi.org/10.1002/jbmr.272