Estrogen receptors’ roles in the control of mechanically adaptive bone (re)modeling

Abstract

The discovery that estrogen receptors (ERs) are involved in bone cells' responses to mechanical strain offered the prospect of establishing the link between declining levels of circulating estrogen and the progressive failure of the mechanically adaptive mechanisms that should maintain structurally appropriate levels of bone mass in age-related and post-menopausal osteoporosis. Such clarification remains elusive but studies have confirmed ligand-independent involvement of ERs as facilitators in a number of the pathways by which mechanical strain stimulates osteoblast proliferation and bone formation. The presence of α and β forms of ER that oppose, supplement or replace one another has complicated interpretation of studies to identify their individual roles when both are present in normal amounts. However, it appears that, in mice at least, ERα promotes cortical bone mass in both males and females through its effects in early members of the osteoblast lineage, but enhances loading-related cortical bone gain only in females. In addition to its role as a potential replacement for ERα, and modifier of ERα activity, the less well-studied ERβ appears to facilitate rapid early effects of strain including activation of extracellular signal-regulated kinase and downregulation of Sost in well-differentiated cells of the osteoblast lineage including osteocytes. If these different roles are substantiated by further studies, it would appear that under normal circumstances ERα contributes primarily to the size and extent of bones' osteogenic response to load bearing through facilitating anabolic influences in osteoblasts and osteoblast progenitors, whereas ERβ is more involved in the strain-related responses generated within resident cells including osteocytes.

Old age and the associated impairment of bones' adaptation to loading are associated with transcriptomic changes in cellular metabolism, cell-matrix interactions and the cell cycle

“…As no curated databases include bone-specific mechanoresponsive signalling pathways, we directly compared the genes regulated by loading at any time point against the list of mechanoresponsive pathway components we previously reported in Galea et al (2013). Loading regulated components of calcium, integrin, estrogen receptor (ER), nitric oxide, prostaglandin (PG), Wnt and IGF signalling cascades in both young and aged mice (Fig.…”

Influence of body weight on bone mass, architecture and turnover

“…Additionally, a strong interaction between weight and estrogen status was identified (Luo, et al 2000; Westerlind, et al 1997). Subsequent ground-based studies in mice further suggest an important role of estrogen receptor signaling in mechanotransduction (Galea, et al 2013; Melville, et al 2015). Finally, although weightlessness and reweighting impact bone mass in opposing directions, the kinetics differ; the time course for bone mass changes during unloading is much more rapid than reloading, implying that factors in addition to mechanostat signaling are involved in mediating skeletal adaptation to changes in weight.…”

Exploiting the WNT Signaling Pathway for Clinical Purposes

“…Weivoda [65] and Tu [62] have provided evidence that loading represses TGFβ signaling through Smad3, which is necessary to induce Sost gene expression and thereby leads to the observed decreases in sclerostin observed in osteocytes following loading. Galea et al [66] have summarized a considerable body of literature implicating important, but varying roles for estrogen receptor mediated regulation in mechanoresponsiveness depending upon the bone cell type/stage of osteoblastic differentiation with ERβ inhibiting Sost gene expression in osteocytes. Other important regulators of Sost gene expression include PTH inhibition involving Mef2c and HDAC4, [67][68][69] calcitonin, [70] BMPs [71][72][73], and 1α,25-dihydroxyvitamin D3 [74,75].…”