Androgen receptor disruption increases the osteogenic response to mechanical loading in male mice

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 remain 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 AR KO 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 AR KO (+320%) and AR-ERalpha KO mice (+256%) compared with male WT mice (+114%) and had a stronger inhibitory effect on SOST/sclerostin expression in AR KO versus 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 AR KO mice. In conclusion, AR but not ERalpha activation limits the osteogenic response to loading in male mice possibly via an effect on WNT signaling.