Transgenic Models of Metabolic Bone Disease: Impact of Estrogen Receptor Deficiency on Skeletal Metabolism

Estrogen has protective effects on the skeleton via its inhibition of bone resorption. Mechanisms for these effects and the selectivity to the estrogen receptor &#102 (ER &#102 ) or ER &#103 are unclear. The purpose of our study was to determine the impact of the ER &#102 on skeletal metabolism using murine models with targeted disruption of the ER &#102 and &#103 . Mice generated by homologous recombination and Cre/ lox P technology yielding a deletion of the ER &#102 exon 3 were evaluated and also crossed with mice with a disruption of the exon 3 of the ER &#103 to result in double ER &#102 and ER &#103 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 &#102 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 &#102 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 &#102 knockout mice was statistically significant. Male double ER &#102 and ER &#103 knockouts had similar reductions in bone density versus the single ER &#102 knockout mice suggesting that the ER &#102 is more protective than the ER &#103 in bone. In vitro analysis revealed no differences in osteoblast differentiation or mineralized nodule formation among cells from ER &#102 genotypes. These data suggest that estrogens are important in skeletal metabolism in males; the ER &#102 plays an important role in estrogen protective effects; osteoblast differentiation is not altered with loss of the ER &#102 ; and compensatory mechanisms are present in the absence of the ER &#102 and/or another receptor for estrogen exists that mediates further effects of estrogen on the skeleton.