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

► We investigate non-DNA binding dependent (DBD) androgen receptor (AR) actions. ► AR from male mice with deletion of the 2nd zinc finger of the DBD (AR ΔZF2) has normal ligand binding ability in vitro. ► AR from AR ΔZF2 mice phosphorylates ERK-1/2 in response to DHT in vitro. ► DHT treatment of AR ΔZF2 male mice suppresses cortical bone growth in vivo. ► Non-DNA binding dependent AR actions oppose classical AR actions in bone. 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 ΔZF2) that cannot bind DNA. In cultured genital skin fibroblasts, the mutant AR ΔZF2 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 ΔZF2 males have normal baseline ERK-1/2 phosphorylation, with a 1.5-fold increase in Akt phosphorylation in AR ΔZF2 muscle vs WT. To identify physiological actions of non-DNA binding-dependent AR signaling, AR ΔZF2 males were treated for 6 weeks with dihydrotestosterone (DHT). Cortical bone growth was suppressed by DHT in AR ΔZF2 mice (6% decrease in periosteal and 7% decrease in medullary circumference vs untreated AR ΔZF2 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.