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

Kristy M. Nicks, Koji Fujita, Daniel Fraser, Ulrike Mcgregor, Matthew M Drake, Meghan E. Mcgee-Lawrence, Jennifer J Westendorf, David G Monroe, Sundeep Khosla

Research output: Contribution to journalArticle

16 Citations (Scopus)

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% [pPrx1-CKO mice, respectively) but no changes in cortical bone. Serum estradiol and IGF-I levels were unaltered in ERβPrx1-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 ERβPrx1-CKO compared with control mice, indicating increased differentiation of osteoblast precursor cells into osteoblasts in ERβPrx1-CKO mice. Detailed quantitative polymerase chain reaction analyses of 128 genes in 16 prespecified pathways revealed significant downregulation of 11 pathways in ERβPrx1-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.

Original languageEnglish (US)
JournalJournal of Bone and Mineral Research
DOIs
StateAccepted/In press - 2015

Fingerprint

Estrogen Receptor beta
Osteoblasts
Bone and Bones
Bone Remodeling
Bone Resorption
Cortical Bone
Serum
Insulin-Like Growth Factor I
Osteogenesis
Knockout Mice
Osteoporosis
Estradiol
Stem Cells
Down-Regulation
Fibroblasts
Bone Marrow
Pharmacology
Phenotype
Polymerase Chain Reaction
Genes

Keywords

  • Bone
  • Estrogen receptor
  • Microstructure

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Deletion of Estrogen Receptor Beta in Osteoprogenitor Cells Increases Trabecular but Not Cortical Bone Mass in Female Mice. / Nicks, Kristy M.; Fujita, Koji; Fraser, Daniel; Mcgregor, Ulrike; Drake, Matthew M; Mcgee-Lawrence, Meghan E.; Westendorf, Jennifer J; Monroe, David G; Khosla, Sundeep.

In: Journal of Bone and Mineral Research, 2015.

Research output: Contribution to journalArticle

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