Control of Bone Anabolism in Response to Mechanical Loading and PTH by Distinct Mechanisms Downstream of the PTH Receptor

Jesus Delgado-Calle, Xiaolin Tu, Rafael Pacheco-Costa, Kevin McAndrews, Rachel Edwards, Gretel G. Pellegrini, Kali Kuhlenschmidt, Naomie Olivos, Alexander Robling, Munro Peacock, Lilian I. Plotkin, Teresita Bellido

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47 Scopus citations

Abstract

Osteocytes integrate the responses of bone to mechanical and hormonal stimuli by poorly understood mechanisms. We report here that mice with conditional deletion of the parathyroid hormone (PTH) receptor 1 (Pth1r) in dentin matrix protein 1 (DMP1)-8kb–expressing cells (cKO) exhibit a modest decrease in bone resorption leading to a mild increase in cancellous bone without changes in cortical bone. However, bone resorption in response to endogenous chronic elevation of PTH in growing or adult cKO mice induced by a low calcium diet remained intact, because the increased bone remodeling and bone loss was indistinguishable from that exhibited by control littermates. In contrast, the bone gain and increased bone formation in cancellous and cortical bone induced by daily injections of PTH and the periosteal bone apposition induced by axial ulna loading were markedly reduced in cKO mice compared to controls. Remarkably, however, wild-type (WT) control littermates and transgenic mice overexpressing SOST injected daily with PTH exhibit similar activation of Wnt/β-catenin signaling, increased bone formation, and cancellous and cortical bone gain. Taken together, these findings demonstrate that Pth1r in DMP1-8kb–expressing cells is required to maintain basal levels of bone resorption but is dispensable for the catabolic action of chronic PTH elevation; and it is essential for the anabolic actions of daily PTH injections and mechanical loading. However, downregulation of Sost/sclerostin, previously shown to be required for bone anabolism induced by mechanical loading, is not required for PTH-induced bone gain, showing that other mechanisms downstream of the Pth1r in DMP1-8kb–expressing cells are responsible for the hormonal effect.

Original languageEnglish (US)
Pages (from-to)522-535
Number of pages14
JournalJournal of Bone and Mineral Research
Volume32
Issue number3
DOIs
StatePublished - Mar 1 2017

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Keywords

  • GENETIC ANIMAL MODELS
  • MOLECULAR PATHWAYS-REMODELING
  • OSTEOCYTES
  • PTH/VITD/FGF23
  • WNT/Β-CATENIN/LRPS

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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