Crosstalk between androgen receptor and protein kinase G signaling in bone: implications for osteoporosis therapy.

Testosterone, the primary androgen in males, is required for optimal bone mass and strength in men, but the benefits of testosterone therapy in elderly men with modestly reduced testosterone levels remain controversial. Androgens enhance bone formation by osteoblasts and inhibit resorption by osteoclasts. Recent data in osteoblasts indicate that rapid extranuclear androgen receptor (AR) signaling enhances nuclear AR-mediated transcription of the skeletal master regulator β-catenin, and boosts cell proliferation, differentiation, and survival. This novel signaling involves nitric oxide (NO), cGMP, and protein kinase G2 (PKG2). We discuss these recent developments and summarize bone-anabolic AR functions and AR/PKG2 interactions as revealed by the phenotypes of Ar and Pkg2 knockout and transgenic mice. We propose that tissue-selective AR modulators and PKG-activating agents may represent novel treatment options for osteoporosis.