Deletion of Estrogen Receptor Beta in Osteoprogenitor Cells Increases Trabecular but Not Cortical Bone Mass in Female Mice.

ABSTRACT: Although the role of ER? in regulating bone metabolism has been extensively studied, ER? has been largely dismissed as a relevant modulator of bone mass. Previous studies examining ER? utilized a germline knockout mouse expressing transcript variants of ER? and displaying systemic hormonal changes that confounded interpretation of the skeletal phenotype. Thus, we used a conditional ER? mouse model to achieve deletion of ER? 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 ER?(Prx1-CKO) mice, respectively) but no changes in cortical bone. Serum estradiol and IGF-I levels were unaltered in ER?(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 ER?(Prx1-CKO) compared with control mice, indicating increased differentiation of osteoblast precursor cells into osteoblasts in ER?(Prx1-CKO) mice. Detailed quantitative polymerase chain reaction analyses of 128 genes in 16 prespecified pathways revealed significant downregulation of 11 pathways in ER?(Prx1-CKO) mice. Thus, deletion of ER? 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 ER? in bone may provide a novel approach to treat osteoporosis.

SUBMITTER: Nicks KM 

PROVIDER: S-EPMC4822412 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature