The Effects of Androgens on Murine Cortical Bone Do Not Require AR or ERα Signaling in Osteoblasts and Osteoclasts

Abstract

In men, androgens are critical for the acquisition and maintenance of bone mass in both the cortical and cancellous bone compartment. Male mice with targeted deletion of the androgen receptor (AR) in mature osteoblasts or osteocytes have lower cancellous bone mass, but no cortical bone phenotype. We have investigated the possibility that the effects of androgens on the cortical compartment result from AR signaling in osteoprogenitors or cells of the osteoclast lineage; or via estrogen receptor alpha (ERα) signaling in either or both of these two cell types upon conversion of testosterone to estradiol. To this end, we generated mice with targeted deletion of an AR or an ERα allele in the mesenchymal (ARf/y;Prx1-Cre or ERαf/f;Osx1-Cre) or myeloid cell lineage (ARf/y; LysM-Cre or ERαf/f;LysM-Cre) and their descendants. Male ARf/y;Prx1-Cre mice exhibited decreased bone volume and trabecular number, and increased osteoclast number in the cancellous compartment. Moreover, they did not undergo the loss of cancellous bone volume and trabecular number caused by orchidectomy (ORX) in their littermate controls. In contrast, ARf/y;LysM-Cre, ERαf/f; Osx1-Cre, or ERαf/f;LysM-Cre mice had no cancellous bone phenotype at baseline and lost the same amount of cancellous bone as their controls following ORX. Most unexpectedly, adult males of all four models had no discernible cortical bone phenotype at baseline, and lost the same amount of cortical bone as their littermate controls after ORX. Recapitulation of the effects of ORX by AR deletion only in the ARf/y;Prx1-Cre mice indicates that the effects of androgens on cancellous bone result from AR signaling in osteoblasts—not on osteoclasts or via aromatization. The effects of androgens on cortical bone mass, on the other hand, do not require AR or ERα signaling in any cell type across the osteoblast or osteoclast differentiation lineage. Therefore, androgens must exert their effects indirectly by actions on some other cell type(s) or tissue(s).

Gonadal steroid–dependent effects on bone turnover and bone mineral density in men

“…In a cohort of men with acquired secondary hypogonadism, whose mean testosterone level was 185 ng/dl, administration of testosterone enanthate increased lumbar spine BMD more than did a placebo (36). Moreover, testosterone administration did bone in male mice (32). In clinical studies, it has been postulated that the effect of androgens on trabecular bone is difficult to detect utilizing biochemical markers of bone resorption because changes in bone resorption markers reflect the effects of gonadal steroids on the entire skeleton, which is mainly composed of cortical bone (31).…”

The androgen receptor has no direct antiresorptive actions in mouse osteoclasts

“…Rankl expression has been found upregulated in osteoblasts of ARKO mice, suggesting that the AR in osteoblasts is critical for the suppressive effect of androgens on osteoclast generation and activity (Kawano et al, 2003). Several animal studies have suggested that the AR might be expressed in osteoclasts and exert effects on these cells in vitro (Huber et al, 2001;Mizuno et al, 1994;Pederson et al, 1999;van der Eerden et al, 2002), although it remains controversial whether the AR inhibits osteoclasts directly. Conditional knockout models have demonstrated that ERα in osteoclasts mediates bone resorption in female but not in male mice (Martin-Millan et al, 2010;Nakamura et al, 2007).…”

Battle of the sex steroids in the male skeleton: and the winner is…

“…Additionally, testosterone deficiency independently predicts fracture risk in some populations (13). Perhaps most convincingly, a recent study in mice supports skeletal site-specific effects of estrogens and androgens by showing that targeted deletion of the murine androgen receptor-encoding gene in osteoblast progenitors compromises trabecular but not cortical bone (24). Conversely, complementary studies in men confirm that serum estradiol is positively associated with cortical thickness and inversely associated with cortical porosity, with evidence of a threshold effect on structural bone parameters, as well (25)(26)(27).…”