Mineralization and Bone Resorption Are Regulated by the Androgen Receptor in Male Mice

Abstract

Androgens play a key role in skeletal growth and bone maintenance; however, their mechanism of action remains unclear. To address this, we selectively deleted the androgen receptor (AR) in terminally differentiated, mineralizing osteoblasts using the Cre/loxP system in mice (osteocalcin-Cre AR knockouts [mOBL-ARKOs]). Male mOBL-ARKOs had decreased femoral trabecular bone volume compared with littermate controls because of a reduction in trabecular number at 6, 12, and 24 wk of age, indicative of increased bone resorption. The effects of AR inactivation in mineralizing osteoblasts was most marked in the young mutant mice at 6 wk of age when rates of bone turnover are high, with a 35% reduction in trabecular bone volume, decreased cortical thickness, and abnormalities in the mineralization of bone matrix, characterized by increased unmineralized bone matrix and a decrease in the amount of mineralizing surface. This impairment in bone architecture in the mOBL-ARKOs persisted throughout adulthood despite an unexpected compensatory increase in osteoblast activity. Our findings show that androgens act through the AR in mineralizing osteoblasts to maintain bone by regulating bone resorption and the coordination of bone matrix synthesis and mineralization, and that this action is most important during times of bone accrual and high rates of bone remodeling.

Inactivation of the androgen receptor in bone-forming cells leads to trabecular bone loss in adult female mice

“…Our results in male mice were in line with those of Chiang et al, 19 who also reported a reduction in Tb.BV in male mice with osteoblast-targeted AR inactivation. However, differing from their results, we did not detect significant differences in cortical bone thickness in male mice.…”

“…Inactivation of the AR DNA-binding activity in osteocalcinexpressing cells 19 and in collagen-1-synthesizing osteoblasts 20 has been shown to reduce trabecular bone volume in male mice. In cortical bone various effects have been reported.…”

Androgen receptor (AR) in osteocytes is important for the maintenance of male skeletal integrity: Evidence from targeted AR disruption in mouse osteocytes

“…(27) Our findings suggest that this age-related decline in trabecular integrity is enhanced by inactivation of the AR in osteocytes, in line with results from previous mice models. (12,13) Studies using the col2.3Cre AR-knockout mice and osteocalcin Cre ARknockout mice also demonstrated that an inactivation of the DNA binding-dependent functions of the AR, specifically in mature osteoblasts of male mice, increases bone resorption and reduces structural integrity of the bone, leading to a similar acceleration of the age-related reduction in trabecular bone volume. (12,13) Expanding the findings of these studies, our current data support the concept that, for the maintenance of the trabecular network after puberty, a functional AR is not only required at the osteoblast stage but also at the osteocyte stage.…”

“…In line with our findings, previous models inactivating the AR at earlier stages of the osteoblast did not observe a significant difference in cortical structure, but mechanical properties were not documented. (12,13) The absence of a major cortical phenotype across a number of similar mice models contrasts with the significant cortical phenotype characterized by reduction of periosteal expansion observed in the ubiquitous ARKO model. (5) Puberty appears to be a critical period for the development of skeletal sexual dimorphism as characterized by wider and longer bones in male.…”

“…In these two models, both the osteoblast and the osteocyte were targeted, which resulted in a trabecular bone phenotype, confirming that the osteoblast and/or osteocyte is a target cell for AR-mediated maintenance of trabecular bone volume. (12,13) Osteoblast development, however, involves three separate stagesproliferation, matrix development, and maturation-as well as mineralization of the bone matrix, (14) and it remains unknown at which stage(s) androgens act. Interestingly, the highest expression of AR has been observed in osteocytes.…”