Androgen receptor SUMOylation regulates bone mass in male mice

The crucial effects of androgens on the male skeleton are at least partly mediated via the androgen receptor (AR). In addition to hormone binding, the AR activity is regulated by post-translational modifications, including SUMOylation. SUMOylation is a reversible modification in which Small Ubiquitin-related MOdifier proteins (SUMOs) are attached to the AR and thereby regulate the activity of the AR and change its interactions with other proteins. To elucidate the importance of SUMOylation of AR for male bone metabolism, we used a mouse model devoid of the two AR SUMOylation sites (AR^SUM-; K381R and K500R are substituted). Six-month-old male AR^SUM- mice displayed significantly reduced trabecular bone volume fraction in the distal metaphyseal region of femur compared with wild type (WT) mice (BV/TV, -19.1 ± 4.9%, P < 0.05). The number of osteoblasts per bone perimeter was substantially reduced (-60.5 ± 7.2%, P < 0.001) while no significant effect was observed on the number of osteoclasts in the trabecular bone of male AR^SUM- mice. Dynamic histomorphometric analysis of trabecular bone revealed a reduced bone formation rate (-32.6 ± 7.4%, P < 0.05) as a result of reduced mineralizing surface per bone surface in AR^SUM- mice compared with WT mice (-24.3 ± 3.6%, P < 0.001). Furthermore, cortical bone thickness in the diaphyseal region of femur was reduced in male AR^SUM- mice compared with WT mice (-7.3 ± 2.0%, P < 0.05). In conclusion, mice devoid of AR SUMOylation have reduced trabecular bone mass as a result of reduced bone formation. We propose that therapies enhancing AR SUMOylation might result in bone-specific anabolic effects with minimal adverse effects in other tissues.