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  • Review Article
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Osteocytic signalling pathways as therapeutic targets for bone fragility

Nature Reviews Endocrinology volume 12, pages 593–605 (2016)Cite this article

Subjects

An Erratum to this article was published on 29 July 2016

This article has been updated

Key Points

  • Osteocytes constitute >95% of the cells in bone

  • Osteocytes are differentiated osteoblasts that live within the bone matrix and are highly connected among themselves and with cells on the bone surface and the bone marrow

  • The molecular and functional signature of osteocytes comprises genes and proteins that control dendritic morphology and canaliculi formation, phosphate metabolism and matrix mineralization, bone formation and bone resorption

  • Osteocytes orchestrate the function of osteoblasts and osteoclasts in response to both mechanical and hormonal cues

  • Osteocytes produce and secrete factors (sclerostin, RANKL and OPG) that affect other bone cells by paracrine and/or autocrine mechanisms and secrete hormones (such as FGF23) that affect other tissues by endocrine mechanisms

  • Novel therapeutic approaches harness the accumulating knowledge of osteocyte biology, thus, targeting osteocytic signalling pathways and messengers to improve skeletal health

Abstract

Osteocytes are differentiated osteoblasts that become surrounded by matrix during the process of bone formation. Acquisition of the osteocyte phenotype is achieved by profound changes in gene expression that facilitate adaptation to the changing cellular environment and constitute the molecular signature of osteocytes. During osteocytogenesis, the expression of genes that are characteristic of the osteoblast are altered and the expression of genes and/or proteins that impart dendritic cellular morphology, regulate matrix mineralization and control the function of cells at the bone surface are ordely modulated. The discovery of mutations in human osteocytic genes has contributed, in a large part, to our understanding of the role of osteocytes in bone homeostasis. Osteocytes are targets of the mechanical force imposed on the skeleton and have a critical role in integrating mechanosensory pathways with the action of hormones, which thereby leads to the orchestrated response of bone to environmental cues. Current, therapeutic approaches harness this accumulating knowledge by targeting osteocytic signalling pathways and messengers to improve skeletal health.

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Figure 1: Osteocytes in the hierarchical organization of bone.
Figure 2: The molecular signature of osteocytes.
Figure 3: Regulation of mineral metabolism by osteocytic proteins.
Figure 4: Osteocyte regulation of bone formation and resorption.
Figure 5: Osteocytic signalling pathways as therapeutic targets.

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Change history

  • 29 July 2016

    Nature Reviews Endocrinology 10.1038/nrendo.2016.71 In Figure 4 of the above article published online 27 May 2016, the label at the bottom of the right side of the figure should have read: Osteoblast generation/survival and bone formation/mineralization. This has been corrected in the online versions of the article.

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Acknowledgements

L.I.P. acknowledges support from the National Institutes of Health (grants R01-AR053643 and R01-AR067210). T.B. acknowledges support from the National Institutes of Health (grants R01-AR059357, R01-DK076007 and S10-RR023710) and the Veteran's Administration Merit Review 1 I01 (grant BX002104-01).

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Authors and Affiliations

  1. Department of Anatomy and Cell Biology, Division of Endocrinology, Indiana University School of Medicine,

    Lilian I. Plotkin & Teresita Bellido

  2. Department of Medicine, Division of Endocrinology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, 46202, Indiana, USA

    Lilian I. Plotkin & Teresita Bellido

  3. Roudebush Veterans Administration Medical Center, 635 Barnhill Drive, Indianapolis, 46202, Indiana, USA

    Teresita Bellido

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  1. Lilian I. Plotkin
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L.I.P. and T.B. made substantial contributions to discussions of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Lilian I. Plotkin or Teresita Bellido.

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PowerPoint slides

Glossary

Osteocytes

Former osteoblasts embedded in the bone matrix that regulate the formation and function of osteoblasts and osteoclasts.

Bone

Specialized connective tissue composed of a mineralized collagen matrix.

Osteoblasts

Bone forming cells.

Osteoclasts

Bone resorbing cells.

Bone formation

The process by which osteoblasts lay down osteoid and its subsequent mineralization.

Bone resorption

The process by which osteoclasts remove mineralized bone.

Mechanical stimulation

Physical force applied to the skeleton that activates intracellular signalling in osteocytes, which in turn transduce these signals into molecular mediators that control the processes of bone formation and resorption.

Sclerostin

Protein produced by mature osteocytes that inhibits canonical Wnt signalling and decreases bone formation.

Parathyroid hormone

Calcium-regulating hormone that is used as a pharmacotherapy to treat osteoporosis and other bone diseases.

Apoptosis

A process by which cells undergo programmed cell death.

Osteoid

Nonmineralized collagenous bone matrix.

Bisphosphonates

Drugs used to treat conditions with low bone mass and increased fracture risk.

Canonical Wnt signalling

Signalling pathway that results from activation of the LRP5/6 and frizzled co-receptors, leading to accumulation of β-catenin, its nuclear translocation and transcription of specific target genes that affect bone formation and resorption.

Glucocorticoids

Hormones secreted from the adrenal gland and used as immunomodulators that profoundly affect bone, decreasing bone mass and increasing the risk of fractures.

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Plotkin, L., Bellido, T. Osteocytic signalling pathways as therapeutic targets for bone fragility. Nat Rev Endocrinol 12, 593–605 (2016). https://doi.org/10.1038/nrendo.2016.71

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