Blockade of receptor-activated Gi signaling in osteoblasts in vivo leads to site-specific increases in cortical and cancellous bone formation

Authors

  • Susan M Millard,

    1. Endocrine Research Unit, Veterans Administration Medical Center and Departments of Medicine and Physiology, University of California San Francisco, San Francisco, CA, USA
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  • Alyssa M Louie,

    1. Endocrine Research Unit, Veterans Administration Medical Center and Departments of Medicine and Physiology, University of California San Francisco, San Francisco, CA, USA
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  • Lalita Wattanachanya,

    1. Endocrine Research Unit, Veterans Administration Medical Center and Departments of Medicine and Physiology, University of California San Francisco, San Francisco, CA, USA
    2. Endocrinology and Metabolism Unit, Department of Medicine, King Chulalongkorn Memorial Hospital, Thai Red Cross Society and Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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  • Thomas J Wronski,

    1. Department of Physiological Sciences, University of Florida, Gainesville, FL, USA
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  • Bruce R Conklin,

    1. Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA
    2. Department of Medicine, University of California San Francisco, San Francisco, CA, USA
    3. Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA
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  • Robert A Nissenson

    Corresponding author
    1. Endocrine Research Unit, Veterans Administration Medical Center and Departments of Medicine and Physiology, University of California San Francisco, San Francisco, CA, USA
    • Veterans Administration Medical Center (111 N), University of California San Francisco, San Francisco, CA 94121, USA.
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Abstract

Osteoblasts play a critical role in the maintenance of bone mass through bone formation and regulation of bone resorption. Targeted expression of a constitutively active engineered Gi-coupled G protein–coupled receptor (GPCR) to osteoblasts in vivo leads to severe osteopenia. However, little is known about the role of endogenous receptor-mediated Gi signaling in regulating osteoblast function. In this study, we investigated the skeletal effects of blocking Gi-coupled signaling in osteoblasts in vivo. This was accomplished by transgenic expression of the catalytic subunit of pertussis toxin (PTX) under control of the collagen Iα 2.3-kb promoter. These mice, designated Col1(2.3)+/PTX+, showed increased cortical thickness at the femoral midshaft at 12 weeks of age. This correlated with increased periosteal bone formation associated with expanded mineralizing surface observed in 8-week-old mice of both genders. The cancellous bone phenotype of the Col1(2.3)+/PTX+ mice was sexually dimorphic, with increases in fractional bone volume at the distal femur seen only in females. Similarly, while cancellous bone-formation rates were unchanged in males, they could not be quantified for female Col1(2.3)+/PTX+ mice owing to the disorganized nature of the labeling pattern, which was consistent with rapid formation of woven bone. Alterations in osteoclast activity did not appear to participate in the phenotype. These data demonstrate that Gi-coupled signaling by GPCRs endogenous to osteoblasts plays a complex role in the regulation of bone formation in a manner that is dependent on both gender and the anatomic site within bone. © 2011 American Society for Bone and Mineral Research.

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