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Submitted on August 28, 2006
Accepted on December 21, 2006
Endocrine Research Unit and Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN; The Jackson Laboratory, Bar Harbor, ME; Institut de Genetique et de Biologie Moleculaire et Cellulaire, Institut Clinique de la Souris, CNRS/INSERM/ULP, College de France, Illkirch Cedex, France; and Department of Endocrinology. Northwestern University, Chicago, IL
* To whom correspondence should be addressed. 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 either through classical ERE pathways or through non-classical, 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 (Non-Classical 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, while the heterozygous ER +/NERKI mice have both one intact ER and one NERKI allele. As compared to ER+/+ litter mates (n = 10/genotype), male ER+/NERKI and ER-/NERKI mice displayed axial and appendicular skeletal osteopenia at 6, 12, 20, and 25 weeks of age, as demonstrated by significant reductions in total BMD at representative sites (aBMD by DXA at the lumbar vertebrae and femur and vBMD by pQCT 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 to 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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