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  • Review Article
  • Published:

The role of estrogen and androgen receptors in bone health and disease

Key Points

  • Estrogen receptor α (ERα)-mediated direct effects of estrogens on osteoclasts, and direct or indirect effects on B lymphocytes, attenuate the resorption of trabecular bone

  • ERα-mediated effects of estrogens on osteoblast progenitors indirectly attenuate resorption at the endocortical surface, via a mechanism initiated outside of the nucleus

  • The ERα of osteoblast progenitors stimulates Wnt signalling and periosteal bone accrual in response to mechanical strain, independently of estrogens

  • The androgen receptor exerts a protective effect on trabecular bone in male mammals, but (unlike estrogen's effects in female mammals), this effect involves actions on osteoblasts and osteocytes

  • Hormonal signals are modified and integrated with various environmental cues in different bone compartments, including mechanical strain, paracrine cytokines and growth factors

Abstract

Mouse models with cell-specific deletion of the estrogen receptor (ER) α, the androgen receptor (AR) or the receptor activator of nuclear factor κB ligand (RANKL), as well as cascade-selective estrogenic compounds have provided novel insights into the function and signalling of ERα and AR. The studies reveal that the effects of estrogens on trabecular versus cortical bone mass are mediated by direct effects on osteoclasts and osteoblasts, respectively. The protection of cortical bone mass by estrogens is mediated via ERα, using a non-nucleus-initiated mechanism. By contrast, the AR of mature osteoblasts is indispensable for the maintenance of trabecular bone mass in male mammals, but not required for the anabolic effects of androgens on cortical bone. Most unexpectedly, and independently of estrogens, ERα in osteoblast progenitors stimulates Wnt signalling and periosteal bone accrual in response to mechanical strain. RANKL expression in B lymphocytes, but not T lymphocytes, contributes to the loss of trabecular bone caused by estrogen deficiency. In this Review, we summarize this evidence and discuss its implications for understanding the regulation of trabecular and cortical bone mass; the integration of hormonal and mechanical signals; the relative importance of estrogens versus androgens in the male skeleton; and, finally, the pathogenesis and treatment of osteoporosis.

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Figure 1: Effects of estrogens and androgens on bone remodelling.
Figure 2: Molecular mechanisms of action of ERα.
Figure 3: Function and signalling mechanisms of ERα and AR in female and male mammals.
Figure 4
Figure 5: Age-related changes in the levels of estrogens, muscle mass and growth factors.

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Acknowledgements

The authors' research is supported by the NIH (grant numbers P01 AG13918, R01 AR56679, and R01 AR49794); the Department of Veterans Affairs from the Biomedical Laboratory Research and Development Service of the Veterans Administration Office of Research and Development to S. C. Manolagas (grant number I01 BX001405) and C. A. O'Brien (grant number I01 BX000294); and the University of Arkansas for Medical Sciences Translational Research Institute and Tobacco Settlement funds. The authors thank Serra Ucer for help with Table 1, Leah Elrod for help with preparation of the manuscript, and A. Michael Parfitt and Robert L. Jilka for critically reviewing it.

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S. C. Manolagas declares that he owns equity in and serves on the scientific advisory board of Radius Health. The other authors declare no competing interests.

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Manolagas, S., O'Brien, C. & Almeida, M. The role of estrogen and androgen receptors in bone health and disease. Nat Rev Endocrinol 9, 699–712 (2013). https://doi.org/10.1038/nrendo.2013.179

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