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PGE2 Receptor Subtype 1 (EP1) Regulates Mesenchymal Stromal Cell Osteogenic Differentiation by Modulating Cellular Energy Metabolism.

Authors
  • Feigenson, Marina1, 2
  • Eliseev, Roman A2
  • Jonason, Jennifer H2
  • Mills, Bradley N3
  • O'Keefe, Regis J4
  • 1 Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, New York 14620.
  • 2 Center for Musculoskeletal Research, University of Rochester School of Medicine and Dentistry, Rochester, New York 14620.
  • 3 Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14620.
  • 4 Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri 63110.
Type
Published Article
Journal
Journal of Cellular Biochemistry
Publisher
Wiley (John Wiley & Sons)
Publication Date
Dec 01, 2017
Volume
118
Issue
12
Pages
4383–4393
Identifiers
DOI: 10.1002/jcb.26092
PMID: 28444901
Source
Medline
Keywords
License
Unknown

Abstract

Mesenchymal stromal cells (MSCs) are multipotent progenitors capable of differentiation into osteoblasts and can potentially serve as a source for cell-based therapies for bone repair. Many factors have been shown to regulate MSC differentiation into the osteogenic lineage such as the Cyclooxygenase-2 (COX2)/Prostaglandin E2 (PGE2) signaling pathway that is critical for bone repair. PGE2 binds four different receptors EP1-4. While most studies focus on the role PGE2 receptors EP2 and EP4 in MSC differentiation, our study focuses on the less studied, receptor subtype 1 (EP1) in MSC function. Recent work from our laboratory showed that EP1-/- mice have enhanced fracture healing, stronger cortical bones, higher trabecular bone volume and increased in vivo bone formation, suggesting that EP1 is a negative regulator of bone formation. In this study, the regulation of MSC osteogenic differentiation by EP1 receptor was investigated using EP1 genetic deletion in EP1-/- mice. The data suggest that EP1 receptor functions to maintain MSCs in an undifferentiated state. Loss of the EP1 receptor changes MSC characteristics and permits stem cells to undergo more rapid osteogenic differentiation. Notably, our studies suggest that EP1 receptor regulates MSC differentiation by modulating MSC bioenergetics, preventing the shift to mitochondrial oxidative phosphorylation by maintaining high Hif1α activity. Loss of EP1 results in inactivation of Hif1α, increased oxygen consumption rate and thus increased osteoblast differentiation. J. Cell. Biochem. 118: 4383-4393, 2017. © 2017 Wiley Periodicals, Inc.

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