Journal of Bone and Mineral Research vol:25 issue:1 pages:124-131
Abstract In female mice, estrogen receptor-alpha (ERalpha) mediates the anabolic response of bone to mechanical loading. Whether ERalpha plays a similar role in the male skeleton, and to what extent androgens and androgen receptor (AR) affect this response in males remains unaddressed. Therefore, we studied the adaptive response of in vivo ulna loading in AR-ERalpha knockout (KO) mice and corresponding male and female single KO and wild-type (WT) littermates, using dynamic histomorphometry and immunohistochemistry. Additionally, cultured bone cells from WT and ARKO mice were subjected to mechanical loading by pulsating fluid flow in the presence or absence of testosterone. In contrast with female mice, ERalpha inactivation in male mice had no effect on the response to loading. Interestingly, loading induced significantly more periosteal bone formation in ARKO (+320%) and AR-ERalphaKO mice (+256%) compared to male WT mice (+114%), and had a stronger inhibitory effect on SOST/sclerostin expression in ARKO vs. WT mice. In accordance, the fluid flow-induced nitric oxide production was higher in the absence of testosterone in bone cells from WT, but not ARKO mice. In conclusion, AR, but not ERalpha activation limits the osteogenic response to loading in male mice, possibly via an effect on Wnt signaling.