A physiological role for androgen actions in the absence of androgen receptor DNA binding activity

We tested the hypothesis that androgens have physiological actions via non-DNA binding-dependent androgen receptor (AR) signaling pathways in males, using our genetically modified mice that express a mutant AR with deletion of the 2nd zinc finger of the DNA binding domain (AR(Delta ZF2)) that cannot bind DNA. In cultured genital skin fibroblasts, the mutant AR(Delta ZF2) has normal ligand binding ability, phosphorylates ERK-1/2 in response to 1 min DHT treatment (blocked by the AR antagonist bicalutamide), but has reduced androgen-dependent nuclear localization compared to wildtype (WT). AR(Delta ZF2) males have normal baseline ERK-1/2 phosphorylation, with a 1.5-fold increase in Akt phosphorylation in AR(Delta ZF2) muscle vs WT. To identify physiological actions of non-DNA binding-dependent AR signaling, AR(Delta ZF2) males were treated for 6 weeks with dihydrotestosterone (DHT). Cortical bone growth was suppressed by DHT in AR(Delta ZF2) mice (6% decrease in periosteal and 7% decrease in medullary circumference vs untreated AR(Delta ZF2) males). In conclusion, these data suggest that non-DNA binding dependent AR actions suppress cortical bone growth, which may provide a mechanism to fine-tune the response to androgens in bone. (C) 2011 Elsevier Ireland Ltd. All rights reserved.