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Effects of Loss of Classical Estrogen Response Element Signaling on Bone in Male Mice

Endocrine Research Unit (F.A.S., D.G.F., S.K.) and Department of Biochemistry and Molecular Biology (T.C.S.), Mayo Clinic College of Medicine, Rochester, Minnesota 55905; The Jackson Laboratory (C.J.R.), Bar Harbor, Maine 04609; Institut de Genetique et de Biologie Moleculaire et Cellulaire (A.K., P.C.), Institut Clinique de la Souris, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université Louis Pasteur, College de France, 75231 Illkirch Cedex, France; and Department of Endocrinology (J.L.J.), Northwestern University, Chicago, Illinois 60208

Address all correspondence and requests for reprints to: Sundeep Khosla, M.D., 5-194 Joseph, Endocrine Research Unit, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905. E-mail: khosla.sundeep{at}mayo.edu.

The role of estrogen signaling in the male skeleton via estrogen receptor (ER)- is now well established. ER 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 ER signaling on the murine male skeleton. To accomplish this, we crossed male mice heterozygous for a knock-in mutation [nonclassical ER knock-in (NERKI)], which abolishes the ERE-mediated pathway with female heterozygous ER knockout mice (ER^+/–) and studied the F1 generation ER^+/+, ER^+/–, ER ^+/NERKI, and ER^–/NERKI male progeny longitudinally using bone density and histomorphometry. The only ER allele present in ER^–/NERKI mice is incapable of classical ERE-mediated signaling, whereas the heterozygous ER^+/NERKI mice have both one intact ER and one NERKI allele. As compared with ER^+/+ littermates (n = 10/genotype), male ER^+/NERKI and ER^–/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. ER^+/+). 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 ER signaling (ER^–/NERKI mice), compared with mice in which one wild-type ER allele was present (ER^+/NERKI mice). Collectively, these data demonstrate that classical ER signaling is crucial for the development of the murine male skeleton.

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