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  • Review Article
  • Published:

The calcium-sensing receptor in bone—mechanistic and therapeutic insights

Nature Reviews Endocrinology volume 11, pages 298–307 (2015)Cite this article

Subjects

Key Points

  • The extracellular calcium-sensing receptor (CaSR) expressed in the parathyroid glands and kidneys modulates blood levels of Ca2+; CaSR is also expressed on bone cells, where it regulates skeletal homeostasis

  • In chondrocytes, CaSR contributes to development of the cartilaginous growth plate, whereas in osteoblasts CaSR is required for the proliferation and differentiation of these cells, and for bone matrix production

  • In young animals, activation of CaSR in osteoclasts inhibits bone resorption, which results in enhanced bone anabolism

  • In old animals, although activation of osteoblasts augments bone formation, this activation also increases the expression of receptor activator of nuclear factor κB ligand and bone resorption by osteoclasts

  • The relationship between activation of CaSR in the skeleton and levels of parathyroid hormone can lead to net bone formation in trabecular bone and net bone resorption in cortical bone

  • Although currently available allosteric modulators of CaSR in the parathyroid gland are beneficial in some clinical conditions, future CaSR-based drugs might be developed that have improved effects on bone

Abstract

The extracellular calcium-sensing receptor, CaSR, is a member of the G protein-coupled receptor superfamily and has a critical role in modulating Ca2+ homeostasis via its role in the parathyroid glands and kidneys. New evidence suggests that CaSR expression in cartilage and bone also directly regulates skeletal homeostasis. This Review discusses the role of CaSR in chondrocytes, through which CaSR contributes to the development of the cartilaginous growth plate, as well as in osteoblasts and osteoclasts, through which CaSR has effects on skeletal development and bone turnover in young and mature animals. The interaction of skeletal CaSR activation with parathyroid hormone (PTH), which is secreted by the parathyroid gland, can lead to net bone formation in trabecular bone or net bone resorption in cortical bone. Allosteric modulators of CaSR are beneficial in some clinical conditions, with effects that are mediated by the ability of these agents to alter levels of PTH and improve Ca2+ homeostasis. However, further insights into the action of CaSR in bone cells might lead to CaSR-based drugs that maximize not only the effects of the receptor on the parathyroid glands and kidneys but also on bone.

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Figure 1: Model of CaSR action in bone formation and resorption.
Figure 2: Model of bone resorptive action of skeletal CaSR in Ca2+ homeostasis.

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Acknowledgements

The authors acknowledge the Canadian Institutes of Health Research for supporting their work.

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Authors and Affiliations

  1. Department of Medicine, McGill University, 687 Pine Avenue West, Montreal, H3A 1A1, QC, Canada

    David Goltzman & Geoffrey N. Hendy

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  1. David Goltzman
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D.G. and G.N.H. researched data for the article, provided substantial contributions to discussions of the content, contributed equally to writing the article, and to review and/or editing of the manuscript before submission.

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Correspondence to Geoffrey N. Hendy.

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Goltzman, D., Hendy, G. The calcium-sensing receptor in bone—mechanistic and therapeutic insights. Nat Rev Endocrinol 11, 298–307 (2015). https://doi.org/10.1038/nrendo.2015.30

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