Estrogen receptor-α is required for the osteogenic response to mechanical loading in a ligand-independent manner involving its activation function 1 but not 2

Abstract

Estrogen receptor-α (ERα) is crucial for the adaptive response of bone to loading but the role of endogenous estradiol (E2) for this response is unclear. To determine in vivo the ligand dependency and relative roles of different ERα domains for the osteogenic response to mechanical loading, gene-targeted mouse models with (1) a complete ERα inactivation (ERα−/−), (2) specific inactivation of activation function 1 (AF-1) in ERα (ERαAF-10), or (3) specific inactivation of ERαAF-2 (ERαAF-20) were subjected to axial loading of tibia, in the presence or absence (ovariectomy [ovx]) of endogenous E2. Loading increased the cortical bone area in the tibia mainly as a result of an increased periosteal bone formation rate (BFR) and this osteogenic response was similar in gonadal intact and ovx mice, demonstrating that E2 (ligand) is not required for this response. Female ERα−/− mice displayed a severely reduced osteogenic response to loading with changes in cortical area (−78% ± 15%, p < 0.01) and periosteal BFR (−81% ± 9%, p < 0.01) being significantly lower than in wild-type (WT) mice. ERαAF-10 mice also displayed a reduced response to mechanical loading compared with WT mice (cortical area −40% ± 11%, p < 0.05 and periosteal BFR −41% ± 8%, p < 0.01), whereas the periosteal osteogenic response to loading was unaffected in ERαAF-20 mice. Mechanical loading of transgenic estrogen response element (ERE)-luciferase reporter mice did not increase luciferase expression in cortical bone, suggesting that the loading response does not involve classical genomic ERE-mediated pathways. In conclusion, ERα is required for the osteogenic response to mechanical loading in a ligand-independent manner involving AF-1 but not AF-2. © 2013 American Society for Bone and Mineral Research

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

“…[35][36][37] In a subsequent study, incomplete deletion of ERb was found to reduce the osteogenic response in the ulna of female mice similarly to ERa deletion, 37 suggesting that the two ERs complemented each other's function in the mechanostat. However, studies using more complete ERb knockout mice suggest an enhanced response to loading in the cortical bone of both male and female mice 36 (Figure 2).…”

“…Windahl et al 35 investigated this by ovariectomizing mice before subjecting their tibiae to loading. Ovariectomy did not alter the loading-related increase in bone formation at either the periosteal or endosteal surface, whereas global deletion of ERa significantly reduced the increase in formation on both surfaces.…”

Estrogen receptor-α in osteocytes is important for trabecular bone formation in male mice

“…Previous studies have demonstrated that female but not male mice with ERα inactivation display reduced cortical osteogenic bone response to mechanical loading (19,(21)(22)(23)(24). In addition, we recently showed that ERα is required for the cortical osteogenic response to mechanical loading in a ligand-independent manner, involving activation function-1 but not activation function-2 in ERα in female mice (20). The primary ERα target cell for this role of ERα in the osteogenic bone response to mechanical loading is not yet characterized, but a plausible candidate is the osteocytes, which are the mechanosensors in bone.…”

“…It is well established that mechanical loading is a major regulator of cortical bone dimensions (19,20). Previous studies have demonstrated that female but not male mice with ERα inactivation display reduced cortical osteogenic bone response to mechanical loading (19,(21)(22)(23)(24).…”

Liver-derived IGF-I regulates cortical bone mass but is dispensable for the osteogenic response to mechanical loading in female mice

“…In vivo tibia loading. The protocol for noninvasively loading the mouse tibia has been reported previously (1,26,37,41). Briefly, while under inhalation anesthesia with Isoflurane (Forene; Abbot Scandinavia, Solna, Sweden), the right tibia of mice aged 6 (control, n ϭ 11; LI-IGF-I Ϫ/Ϫ , n ϭ 9) or 19 mo (control, n ϭ 8; LI-IGF-I Ϫ/Ϫ , n ϭ 7) was axially loaded on 3 alternate days/wk for 2 wk (days 1, 3,5,8,10, and 12) for 40 cycles/day with a trapezoid waveform, with 10 s of rest between cycles.…”