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Abstract
Estrogen has protective effects on the skeleton via its inhibition of bone resorption. Mechanisms for these effects and the selectivity to the estrogen receptor f (ER f ) or ER g are unclear. The purpose of our study was to determine the impact of the ER f on skeletal metabolism using murine models with targeted disruption of the ER f and g . Mice generated by homologous recombination and Cre/ lox P technology yielding a deletion of the ER f exon 3 were evaluated and also crossed with mice with a disruption of the exon 3 of the ER g to result in double ER f and ER g knockout mice. Skeletal analysis of long bone length and width, radiographs, dual X-ray absorptiometry, bone histomorphometry, micro computerized tomography, biomechanical analysis, serum biochemistry, and osteoblast differentiation were evaluated. Male ER f knockout mice had the most dramatic phenotype consisting of reduced bone mineral density (BMD), and bone mineral content (BMC) of femurs at 10 and 16 weeks and 8-9 months of age. Female ER f knockout mice also had reduced density of long bones but to a lesser degree than male mice. The reduction of trabecular and cortical bone in male ER f knockout mice was statistically significant. Male double ER f and ER g knockouts had similar reductions in bone density versus the single ER f knockout mice suggesting that the ER f is more protective than the ER g in bone. In vitro analysis revealed no differences in osteoblast differentiation or mineralized nodule formation among cells from ER f genotypes. These data suggest that estrogens are important in skeletal metabolism in males; the ER f plays an important role in estrogen protective effects; osteoblast differentiation is not altered with loss of the ER f ; and compensatory mechanisms are present in the absence of the ER f and/or another receptor for estrogen exists that mediates further effects of estrogen on the skeleton.