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 Plotkin, Teresita Bellido

Research output: Contribution to journalArticle

30 Citations (Scopus)

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)
JournalJournal of Bone and Mineral Research
DOIs
StateAccepted/In press - 2016

Fingerprint

Parathyroid Hormone Receptor Type 1
Parathyroid Hormone
Bone and Bones
Dentin
Bone Resorption
Osteogenesis
Osteocytes
Catenins
Ulna
Injections
Proteins
Bone Remodeling
Weight-Bearing
Transgenic Mice
Down-Regulation
Diet
Calcium

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

Cite this

Control of Bone Anabolism in Response to Mechanical Loading and PTH by Distinct Mechanisms Downstream of the PTH Receptor. / Delgado-Calle, Jesus; Tu, Xiaolin; Pacheco-Costa, Rafael; Mcandrews, Kevin; Edwards, Rachel; Pellegrini, Gretel G.; Kuhlenschmidt, Kali; Olivos, Naomie; Robling, Alexander; Peacock, Munro; Plotkin, Lilian; Bellido, Teresita.

In: Journal of Bone and Mineral Research, 2016.

Research output: Contribution to journalArticle

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AU - Tu, Xiaolin

AU - Pacheco-Costa, Rafael

AU - Mcandrews, Kevin

AU - Edwards, Rachel

AU - Pellegrini, Gretel G.

AU - Kuhlenschmidt, Kali

AU - Olivos, Naomie

AU - Robling, Alexander

AU - Peacock, Munro

AU - Plotkin, Lilian

AU - Bellido, Teresita

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