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Regulation of Sclerostin Expression by Paracrine and Endocrine Factors

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Abstract

Sclerostin, a secreted protein encoded by the SOST gene, has been identified as a key regulator of bone formation by studies in human and mouse genetics. Expression of this protein in osteocytes has been shown to be regulated by mechanical forces, and this has been shown to be critical for the bone formation response to load. Osteocytic expression of sclerostin is also regulated by systemic hormones that are known to influence the skeleton including parathyroid hormone and calcitonin. Circulating levels of sclerostin appear to be influenced by circulating sex steroid levels. Paracrine and autocrine factors expressed by the cells within bone (osteoblasts, osteoclasts and osteocytes), including some members of the family of cytokines that signal through gp130 (oncostatin M, cardiotrophin-1 and leukemia inhibitory factor) as well as prostaglandin E2, rapidly regulate osteocytic sclerostin expression, pointing to new paracrine networks within the bone matrix. In addition, regulation of sclerostin by osteoblastic transcription factors, such as osterix and zinc finger protein 467, has been identified. Finally, changes in sclerostin expression due to changes in osteoblast differentiation have been reported in response to inhibitors of ephrin signaling and in response to the inflammatory mediators tumor necrosis factor and TWEAK. This review will discuss the evidence for each of these influences and what they might mean for bone physiology.

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Abbreviations

α-CGRP:

Alpha calcitonin gene-related peptide

CNTFR:

Ciliary neurotrophic factor receptor

CT:

Calcitonin

CT-1:

Cardiotrophin-1

EP:

Prostaglandin E series receptors

GnRH:

Gonadotrophin-releasing hormone

gp130:

Glycoprotein 130

IL-33:

Interleukin-33

LIF:

Leukemia inhibitory factor

LIFR:

Leukemia inhibitory factor receptor

LRP:

Low-density lipoprotein-related protein

M-CSF:

Macrophage colony stimulating factor

MEF2:

Myocyte enhancer factor 2

OPG:

Osteoprotegerin

OSM:

Oncostatin M

OSMR:

Oncostatin M receptor

PTH:

Parathyroid hormone

PTHrP:

Parathyroid hormone-related peptide

PTHR1:

Parathyroid hormone receptor 1

RANKL:

Receptor activator of NFΚB ligand

sCT:

Salmon calcitonin

TNFα:

Tumor necrosis factor α

TWEAK:

TNF-related weak inducer of apoptosis

Zfp467:

Zinc finger protein 467

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Acknowledgments

Thanks to Damien Genetos for helpful information on non-osteocyte-specific expression of sclerostin and to Jack Martin for critical reading of this manuscript.

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Authors and Affiliations

  1. St. Vincent’s Institute of Medical Research, 9 Princes St, Fitzroy, VIC, 3065, Australia

    Natalie A. Sims & Ling Yeong Chia

  2. Department of Medicine at St. Vincent’s Hospital, The University of Melbourne, Fitzroy, VIC, 3065, Australia

    Natalie A. Sims & Ling Yeong Chia

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  1. Natalie A. Sims
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  2. Ling Yeong Chia
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Correspondence to Natalie A. Sims.

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Sims, N.A., Chia, L.Y. Regulation of Sclerostin Expression by Paracrine and Endocrine Factors. Clinic Rev Bone Miner Metab 10, 98–107 (2012). https://doi.org/10.1007/s12018-011-9121-7

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  • DOI: https://doi.org/10.1007/s12018-011-9121-7

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