The role of estrogen signaling in the male skeleton via estrogen receptor (ER)-α is now well established. ERα can elicit responses through either classical estrogen response elements (ERE) pathways or nonclassical, non-ERE pathways. In the present study, we examined the effects of either the attenuation or loss of classical ERα signaling on the murine male skeleton. To accomplish this, we crossed male mice heterozygous for a knock-in mutation [nonclassical ERα knock-in (NERKI)], which abolishes the ERE-mediated pathway with female heterozygous ERα knockout mice (ERα+/-) and studied the F1 generation ERα+/+, ERα+/-, ERα+/NERKI, and ERα -/NERKI male progeny longitudinally using bone density and histomorphometry. The only ERα allele present in ERα -/NERKI mice is incapable of classical ERE-mediated signaling, whereas the heterozygous ERα+/NERKI mice have both one intact ERα and one NERKI allele. As compared with ERα+/+ littermates (n = 10/genotype), male ERα+/NERKI and ERα-/NERKI mice displayed axial and appendicular skeletal osteopenia at 6, 12, 20, and 25 wk of age, as demonstrated by significant reductions in total bone mineral density (BMD) at representative sites (areal BMD by dual-energy x-ray absorptiometry at the lumbar vertebrae and femur and volumetric BMD by peripheral quantitative computed tomography at the tibia; P < 0.05-0.001 vs. ERα+/+). The observed osteopenia in these mice was evident in both trabecular and cortical bone compartments. However, these decreases were more severe in mice lacking classical ERα signaling (ERα-/NERKI mice), compared with mice in which one wild-type ERα allele was present (ERα+/NERKI mice). Collectively, these data demonstrate that classical ERα signaling is crucial for the development of the murine male skeleton.
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