Differential regulation of bone and body composition in male mice with combined inactivation of androgen and estrogen receptor-α

Osteoporosis and muscle frailty are important health problems in elderly men and may be partly related to biological androgen activity. This androgen action can be mediated directly through stimulation of the androgen receptor (AR) or indirectly through stimulation of estrogen receptor-alpha (ER alpha) following aromatization of androgens into estrogens. To assess the differential action of AR and ER alpha pathways on bone and body composition, AR-ER alpha double-knockout mice were generated and characterized. AR disruption decreased trabecular bone mass, whereas ER alpha disruption had no additional effect on the AR-dependent trabecular bone loss. In contrast, combined AR and ER alpha inactivation additionally reduced cortical bone and muscle mass compared with either AR or ER alpha disruption alone. ER alpha inactivation-in the presence or absence of AR-increased fat mass. We demonstrate that AR activation is solely responsible for the development and maintenance of male trabecular bone mass. Both AR and ER alpha activation, however, are needed to optimize the acquisition of cortical bone and muscle mass. ER alpha activation alone is sufficient for the regulation of fat mass. Our findings clearly define the relative importance of AR and ER alpha signaling on trabecular and cortical bone mass as well as body composition in male mice.-Callewaert, F., Venken, K., Ophoff, J., De Gendt, K., Torcasio, A., van Lenthe, G. H., Van Oosterwyck, H., Boonen, S., Bouillon, R., Verhoeven, G., Vanderschueren, D. Differential regulation of bone and body composition in male mice with combined inactivation of androgen and estrogen receptor-alpha. FASEB J. 23, 232-240 (2009)