title: Deletion of Estrogen Receptor Beta in Osteoprogenitor Cells Increases Trabecular but Not Cortical Bone Mass in Female Mice.
abstract: Although the role of ERα in regulating bone metabolism has been extensively studied, ERβ has been largely dismissed as a relevant modulator of bone mass. Previous studies examining ERβ utilized a germline knockout mouse expressing transcript variants of ERβ and displaying systemic hormonal changes that confounded interpretation of the skeletal phenotype. Thus, we used a conditional ERβ mouse model to achieve deletion of ERβ specifically in early osteoprogenitor cells using the Prx1-Cre driver. We observed marked increases in the trabecular bone volume fraction (of 58% [p < 0.003] and 93% [p < 0.0003] in 6- and 12-week-old female ERβ(Prx1-CKO) mice, respectively) but no changes in cortical bone. Serum estradiol and IGF-I levels were unaltered in ERβ(Prx1-CKO) mice. Bone formation and resorption indices by histomorphometry and serum assays were unchanged in these mice, suggesting that alterations in bone turnover may have occurred early in development. However, the ratio of colony-forming unit-osteoblasts (CFU-OBs) to CFU-fibroblasts (CFU-Fs) was increased in bone marrow cultures from ERβ(Prx1-CKO) compared with control mice, indicating increased differentiation of osteoblast precursor cells into osteoblasts in ERβ(Prx1-CKO) mice. Detailed quantitative polymerase chain reaction analyses of 128 genes in 16 prespecified pathways revealed significant downregulation of 11 pathways in ERβ(Prx1-CKO) mice. Thus, deletion of ERβ specifically in osteoblast lineage cells, in the absence of all splice variants, increases trabecular bone mass and modulates multiple pathways related to bone metabolism. These findings suggest that pharmacological inhibition of ERβ in bone may provide a novel approach to treat osteoporosis.
authors.affiliation: Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Kristy M
authors.initials: KM
authors.lastname: Nicks
authors.affiliation: Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Koji
authors.initials: K
authors.lastname: Fujita
authors.affiliation: Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Fraser
authors.affiliation: Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Ulrike
authors.initials: U
authors.lastname: McGregor
authors.affiliation: Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Drake
authors.affiliation: Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Meghan E
authors.initials: ME
authors.lastname: McGee-Lawrence
authors.affiliation: Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Westendorf
authors.affiliation: Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Monroe
authors.affiliation: Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Sundeep
authors.initials: S
authors.lastname: Khosla
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000166:cytology*; D000071556:Cancellous Bone / Q000033:anatomy & histology*; D002454:Cell Differentiation; D002460:Cell Line; D003114:Colony-Forming Units Assay; D000071538:Cortical Bone / Q000033:anatomy & histology*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size; D010006:Osteoblasts / Q000378:metabolism; D010052:Ovariectomy; D013234:Stem Cells / Q000378:metabolism*; D055114:X-Ray Microtomography
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta
keywords: BONE; ESTROGEN RECEPTOR; MICROSTRUCTURE