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

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.

Figure 1

Effects of estrogens and androgens on bone remodelling. Osteoclasts and osteoblasts are derived from haematopoietic and mesenchymal precursors, respectively. During the process of bone remodelling, bone matrix excavated by osteoclasts is replaced with new matrix produced by osteoblasts. Both estrogens and androgens influence the differentiation of osteoclast and osteoblast precursors and the lifespan of mature osteoclasts and osteoblasts, as well as the lifespan of osteocytes. Positive (black arrows) and negative (red bars) effects on the cells are depicted as well as differentiation of cells (dashed arrows).

Figure 2

Molecular mechanisms of action of ERα. a | Classic genomic signalling, in which ligand-activated ERα dimers attach to EREs on DNA and activate or repress transcription. b | ERE-independent genomic signalling, in which ligand-activated ERα binds to other transcription factors (such as the p50 and p65 subunits of NF-κB), which prevent them from binding to their response elements. c,d | Nongenotropic mode of action, in which ligand-activated ERα (in the plasma membrane) activates cytoplasmic kinases which, in turn, induce the phosphorylation of substrate proteins and transcription factors (such as Elk-1 and AP-1) that (c) positively or (d) negatively regulate transcription. Abbreviations: AP-1, transcription factor AP-1; CoA, coenzyme A; Elk-1, ETS domain-containing protein Elk-1; ERα, estrogen receptor α; ERE, estrogen response element; Shc, Shc-transforming protein; SRE, serum response element.

Figure 3

Function and signalling mechanisms of ERα and AR in female and male mammals. Effects on different cell types were determined using mouse models of cell-specific deletions. Non-nuclear-initiated signalling mechanisms were elucidated using cascade-selective estrogenic compounds.

Figure 4

Effects of sex steroid hormones and their receptors on bone.

Figure 5

Age-related changes in the levels of estrogens, muscle mass and growth factors. The Figure is based on data from two studies.^,