The skeleton is one of the main targets of estrogen (E) action, as E regulates bone growth and remodeling. Although decreased E levels are known to be one of the main causes of osteoporosis, the specific molecular pathways by which E regulates bone metabolism are not fully characterized or understood. This Project uses a combination of novel mouse and cell models to define, at the cellular and molecular level, the signaling pathways by which E regulates bone turnover and bone mass, focusing on two modalities by which the estrogen receptor-alpha (ERa) functions: the classical mode of action, where ERa directly interacts with estrogen response elements (EREs) on DMA, and the non-classical mode, where ERa indirectly functions through protein-protein interactions with other transcription factors. Preliminary data demonstrates that mice containing an ERa mutation that eliminates classical ERa signaling (NERKI) exhibit osteopenia and impaired bone formation in both cortical and trabecular bone in males, but only in cortical bone in females. We hypothesize that due to increased E levels in female mice, ER(3 functions to mitigate the negative effects of the NERKI receptor in trabecular bone.
In Aim 1, we directly test this by assessing whether loss of ERB leads to greater skeletal deficits in female, but not male NERKI mice. We will examine bones from wild type, NERKI//ERB+/+, and NERKI//ERB-/- mice using bone densitometry and histomorphometry.
Aim 2 tests this hypothesis at the cellular level by assessing the ability of bone marrow stromal cells from these mice to commit and differentiate along the osteoblast lineage. Using quantitative polymerase chain reaction assays, we will test the hypotheses that expression of the NERKI receptor leads to impaired responses to Wnts and BMPs, and that ERP modulates these effects.
Aim 3 examines loss of classical ERa signaling on the recruitment of the NERKI receptor to non-classical DNA binding sites using chromatin immunoprecipitation assays. Finally, Aim 4 uses a novel transgenic approach to examine the skeletal consequences of selective replacement of the endogenous ERa with the NERKI receptor only in osteoblasts. Collectively, these studies will provide a more detailed understanding of ER signaling pathways in bone.

Public Health Relevance

Decreased E levels are known to be one of the main causes of osteoporosis following the menopause. The understanding of how E affects the skeleton through the various ERa signaling pathways (classical versus non-classical) will allow for a better definition of the mechanisms of bone loss and lead to the development of new approaches to prevent and treat osteoporosis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG004875-30
Application #
8494476
Study Section
Special Emphasis Panel (ZAG1-ZIJ-8)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
30
Fiscal Year
2013
Total Cost
$254,438
Indirect Cost
$86,047
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Drake, Matthew T; Khosla, Sundeep (2016) Hormonal and systemic regulation of sclerostin. Bone :
Rocca, Walter A; Gazzuola-Rocca, Liliana; Smith, Carin Y et al. (2016) Accelerated Accumulation of Multimorbidity After Bilateral Oophorectomy: A Population-Based Cohort Study. Mayo Clin Proc 91:1577-1589
McGee-Lawrence, Meghan E; Carpio, Lomeli R; Schulze, Ryan J et al. (2016) Hdac3 Deficiency Increases Marrow Adiposity and Induces Lipid Storage and Glucocorticoid Metabolism in Osteochondroprogenitor Cells. J Bone Miner Res 31:116-28
Farr, Joshua N; Khosla, Sundeep (2016) Determinants of bone strength and quality in diabetes mellitus in humans. Bone 82:28-34
Sellmeyer, Deborah E; Civitelli, Roberto; Hofbauer, Lorenz C et al. (2016) Skeletal Metabolism, Fracture Risk, and Fracture Outcomes in Type 1 and Type 2 Diabetes. Diabetes 65:1757-66
Nicks, Kristy M; Fujita, Koji; Fraser, Daniel et al. (2016) Deletion of Estrogen Receptor Beta in Osteoprogenitor Cells Increases Trabecular but Not Cortical Bone Mass in Female Mice. J Bone Miner Res 31:606-14
Schafer, Marissa J; Atkinson, Elizabeth J; Vanderboom, Patrick M et al. (2016) Quantification of GDF11 and Myostatin in Human Aging and Cardiovascular Disease. Cell Metab 23:1207-15
Weivoda, Megan M; Ruan, Ming; Hachfeld, Christine M et al. (2016) Wnt Signaling Inhibits Osteoclast Differentiation by Activating Canonical and Noncanonical cAMP/PKA Pathways. J Bone Miner Res 31:65-75
Weivoda, Megan M; Ruan, Ming; Pederson, Larry et al. (2016) Osteoclast TGF-β Receptor Signaling Induces Wnt1 Secretion and Couples Bone Resorption to Bone Formation. J Bone Miner Res 31:76-85
Roforth, Matthew M; Farr, Joshua N; Fujita, Koji et al. (2015) Global transcriptional profiling using RNA sequencing and DNA methylation patterns in highly enriched mesenchymal cells from young versus elderly women. Bone 76:49-57

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