title: Effects of loss of classical estrogen response element signaling on bone in male mice.
abstract: The role of estrogen signaling in the male skeleton via estrogen receptor (ER)-alpha is now well established. ERalpha 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 ERalpha signaling on the murine male skeleton. To accomplish this, we crossed male mice heterozygous for a knock-in mutation [nonclassical ERalpha knock-in (NERKI)], which abolishes the ERE-mediated pathway with female heterozygous ERalpha knockout mice (ERalpha+/-) and studied the F1 generation ERalpha+/+, ERalpha+/-, ERalpha+/NERKI, and ERalpha-/NERKI male progeny longitudinally using bone density and histomorphometry. The only ERalpha allele present in ERalpha-/NERKI mice is incapable of classical ERE-mediated signaling, whereas the heterozygous ERalpha+/NERKI mice have both one intact ERalpha and one NERKI allele. As compared with ERalpha+/+ littermates (n=10/genotype), male ERalpha+/NERKI and ERalpha-/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. ERalpha+/+). 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 ERalpha signaling (ERalpha-/NERKI mice), compared with mice in which one wild-type ERalpha allele was present (ERalpha+/NERKI mice). Collectively, these data demonstrate that classical ERalpha signaling is crucial for the development of the murine male skeleton.
authors.affiliation: Endocrine Research Unit, Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905, USA.
authors.forename: Farhan A
authors.initials: FA
authors.lastname: Syed
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Fraser
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Spelsberg
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Rosen
authors.forename: Andree
authors.initials: A
authors.lastname: Krust
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: J Larry
authors.initials: JL
authors.lastname: Jameson
authors.forename: Sundeep
authors.initials: S
authors.lastname: Khosla
mesh_terms: D000818:Animals; D001835:Body Weight; D015519:Bone Density; D001846:Bone Development / Q000235:genetics; D001842:Bone and Bones / Q000033:anatomy & histology* / Q000378:metabolism; D019245:Compressive Strength; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D008159:Lumbar Vertebrae / Q000033:anatomy & histology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020218:Response Elements / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D047628:Estrogen Receptor alpha