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

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Original Article

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

Filip Callewaert¹, Astrid Bakker², Jan Schrooten³, Bart Van Meerbeek⁴, Guido Verhoeven¹, Steven Boonen¹, Dirk Vanderschueren^{1 *}

¹Center for Musculoskeletal Research, Department of Experimental Medicine, Katholieke Universiteit Leuven, Leuven, Belgium
²Department of Oral Cell Biology, ACTA-University of Amsterdam and VU University Amsterdam, Research Institute MOVE, Amsterdam, The Netherlands
³Department of Metallurgy and Materials Engineering, Katholieke Universiteit Leuven, Leuven, Belgium
⁴Leuven BIOMAT Research Cluster, Department of Conservative Dentistry, Katholieke Universiteit Leuven, Leuven, Belgium

email: Dirk Vanderschueren (Dirk.Vanderschueren@uz.kuleuven.be)

^*Correspondence to Dirk Vanderschueren, Center for Musculoskeletal Research, Herestraat 49, B-3000 Leuven, Belgium.

Keywords

sex steroid receptors adaptive response of bone to mechanical loading bone formation SOST/sclerostin pulsating fluid flow

Abstract

In female mice, estrogen receptor-alpha (ER

) mediates the anabolic response of bone to mechanical loading. Whether ER

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-ER

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, ER

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-ER

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 ER

Received: 3 August 2009; Revised: 1 October 2009; Accepted: 9 October 2009

Digital Object Identifier (DOI)

10.1359/jbmr.091001 About DOI