Loss of Gi G‐Protein‐Coupled Receptor Signaling in Osteoblasts Accelerates Bone Fracture Healing |
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| Authors: | Shirley Lieu Mark Scott Dylan O'Carroll Ashley Urrutia Bruce R Conklin Celine Colnot Robert A Nissenson |
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| Affiliation: | 1. Department of Orthopedic Surgery, University of California, San Francisco General Hospital, Orthopaedic Trauma Institute, San Francisco, CA;2. Endocrine Research Unit, VA Medical Center and Departments of Medicine and Physiology, University of California, San Francisco, CA;3. Department of Medicine, the Program in Craniofacial Biology, and the Institute for Human Genetics, University of California, San Francisco, CA;4. Gladstone Institute of Cardiovascular Disease, San Francisco, CA;5. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA;6. Institut National de la Santé et de la Recherche Médicale (INSERM;7. National Institute of Health and Medical Research), Unités Mixtes de Recherche (UMR) 1163, Université Paris Descartes‐Sorbonne Paris Cité, Institut Imagine, Paris, France |
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| Abstract: | G‐protein‐coupled receptors (GPCRs) are key regulators of skeletal homeostasis and are likely important in fracture healing. Because GPCRs can activate multiple signaling pathways simultaneously, we used targeted disruption of Gi‐GPCR or activation of Gs‐GPCR pathways to test how each pathway functions in the skeleton. We previously demonstrated that blockade of Gi signaling by pertussis toxin (PTX) transgene expression in maturing osteoblastic cells enhanced cortical and trabecular bone formation and prevented age‐related bone loss in female mice. In addition, activation of Gs signaling by expressing the Gs‐coupled engineered receptor Rs1 in maturing osteoblastic cells induced massive trabecular bone formation but cortical bone loss. Here, we test our hypothesis that the Gi and Gs pathways also have distinct functions in fracture repair. We applied closed, nonstabilized tibial fractures to mice in which endogenous Gi signaling was inhibited by PTX, or to mice with activated Gs signaling mediated by Rs1. Blockade of endogenous Gi resulted in a smaller callus but increased bone formation in both young and old mice. PTX treatment decreased expression of Dkk1 and increased Lef1 mRNAs during fracture healing, suggesting a role for endogenous Gi signaling in maintaining Dkk1 expression and suppressing Wnt signaling. In contrast, adult mice with activated Gs signaling showed a slight increase in the initial callus size with increased callus bone formation. These results show that Gi blockade and Gs activation of the same osteoblastic lineage cell can induce different biological responses during fracture healing. Our findings also show that manipulating the GPCR/cAMP signaling pathway by selective timing of Gs and Gi‐GPCR activation may be important for optimizing fracture repair. © 2015 American Society for Bone and Mineral Research. |
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| Keywords: | G‐PROTEIN‐COUPLED RECEPTOR SIGNALING OSTEOBLASTIC CELLS FRACTURE REPAIR |
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