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

Estrogen receptor-alpha (ER alpha) 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 ERa domains for the osteogenic response to mechanical loading, gene-targeted mouse models with (1) a complete ERa inactivation (ER alpha(-/-)), (2) specific inactivation of activation function 1 (AF-1) in ER alpha (ER alpha AF-1(0)), or (3) specific inactivation of ER alpha AF-2 (ER alpha AF- 2(0)) 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 ER alpha(-/-) 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. ER alpha AF-1(0) 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 ER alpha AF-2(0) 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, ERa is required for the osteogenic response to mechanical loading in a ligand-independent manner involving AF-1 but not AF-2. (C) 2013 American Society for Bone and Mineral Research.