PTH receptor signaling in osteocytes governs periosteal bone formation and intracortical remodeling

Authors

  • Yumie Rhee,

    1. Department of Anatomy and Cell Biology, Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, USA
    Current affiliation:
    1. Yumie Rhee, Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, Korea.
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  • Matthew R Allen,

    1. Department of Anatomy and Cell Biology, Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, USA
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  • Keith Condon,

    1. Department of Anatomy and Cell Biology, Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, USA
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  • Virginia Lezcano,

    1. Department of Anatomy and Cell Biology, Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, USA
    Current affiliation:
    1. Virginia Lezcano, Ana C Ronda, Department of Biochemistry, Biology, and Pharmacy, Universidad Nacional del Sur, Bahía Blanca, Argentina.
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  • Ana C Ronda,

    1. Department of Anatomy and Cell Biology, Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, USA
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  • Carlo Galli,

    1. Department of Anatomy and Cell Biology, Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, USA
    Current affiliation:
    1. Carlo Galli, Giovanni Passeri, Department of Internal Medicine and Biomedical Sciences, Center for Metabolic Bone Diseases, University of Parma, Italy.
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  • Naomi Olivos,

    1. Department of Anatomy and Cell Biology, Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, USA
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  • Giovanni Passeri,

    1. Department of Anatomy and Cell Biology, Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, USA
    Current affiliation:
    1. Carlo Galli, Giovanni Passeri, Department of Internal Medicine and Biomedical Sciences, Center for Metabolic Bone Diseases, University of Parma, Italy.
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  • Charles A O'Brien,

    1. Department of Medicine, Division of Endocrinology, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR, USA
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  • Nicoletta Bivi,

    1. Department of Anatomy and Cell Biology, Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, USA
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  • Lilian I Plotkin,

    1. Department of Anatomy and Cell Biology, Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, USA
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  • Teresita Bellido

    Corresponding author
    1. Department of Anatomy and Cell Biology, Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, USA
    2. Department of Medicine, Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, USA
    • Department of Anatomy and Cell Biology and Department of Internal Medicine, Division of Endocrinology, Indiana University School of Medicine, 635 Barnhill Drive, MS5035, Indianapolis, IN 46202, USA.
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Abstract

The periosteal and endocortical surfaces of cortical bone dictate the geometry and overall mechanical properties of bone. Yet the cellular and molecular mechanisms that regulate activity on these surfaces are far from being understood. Parathyroid hormone (PTH) has profound effects in cortical bone, stimulating periosteal expansion and at the same time accelerating intracortical bone remodeling. We report herein that transgenic mice expressing a constitutive active PTH receptor in osteocytes (DMP1-caPTHR1 mice) exhibit increased cortical bone area and an elevated rate of periosteal and endocortical bone formation. In addition, DMP1-caPTHR1 mice display a marked increase in intracortical remodeling and cortical porosity. Crossing DMP1-caPTHR1 mice with mice lacking the Wnt coreceptor, LDL-related receptor 5 (LRP5), or with mice overexpressing the Wnt antagonist Sost in osteocytes (DMP1-Sost mice) reduced or abolished, respectively, the increased cortical bone area, periosteal bone formation rate, and expression of osteoblast markers and Wnt target genes exhibited by the DMP1-caPTHR1 mice. In addition, DMP1-caPTHR1 lacking LRP5 or double transgenic DMP1-caPTHR1;DMP1-Sost mice exhibit exacerbated intracortical remodeling and increased osteoclast numbers, and markedly decreased expression of the RANK decoy receptor osteoprotegerin. Thus, whereas Sost downregulation and the consequent Wnt activation is required for the stimulatory effect of PTH receptor signaling on periosteal bone formation, the Wnt-independent increase in osteoclastogenesis induced by PTH receptor activation in osteocytes overrides the effect on Sost. These findings demonstrate that PTH receptor signaling influences cortical bone through actions on osteocytes and defines the role of Wnt signaling in PTH receptor action. © 2011 American Society for Bone and Mineral Research.

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