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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-8)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mayo Clinic, Rochester
United States
Zip Code
Xu, Ming; Pirtskhalava, Tamar; Farr, Joshua N et al. (2018) Senolytics improve physical function and increase lifespan in old age. Nat Med 24:1246-1256
Khosla, Sundeep; Farr, Joshua N; Kirkland, James L (2018) Inhibiting Cellular Senescence: A New Therapeutic Paradigm for Age-Related Osteoporosis. J Clin Endocrinol Metab 103:1282-1290
Rocca, Walter A (2018) The future burden of Parkinson's disease. Mov Disord 33:8-9
Rocca, Walter A; Gazzuola Rocca, Liliana; Smith, Carin Y et al. (2018) Personal, reproductive, and familial characteristics associated with bilateral oophorectomy in premenopausal women: A population-based case-control study. Maturitas 117:64-77
Drake, Matthew T; Fenske, Jennifer S; Blocki, Frank A et al. (2018) Validation of a novel, rapid, high precision sclerostin assay not confounded by sclerostin fragments. Bone 111:36-43
Laughlin-Tommaso, Shannon K; Khan, Zaraq; Weaver, Amy L et al. (2018) Cardiovascular and metabolic morbidity after hysterectomy with ovarian conservation: a cohort study. Menopause 25:483-492
Farr, Joshua N; Weivoda, Megan M; Nicks, Kristy M et al. (2018) Osteoprotection Through the Deletion of the Transcription Factor Ror? in Mice. J Bone Miner Res 33:720-731
Wenning, Gregor; Trojanowski, John Q; Kaufmann, Horacio et al. (2018) Is multiple system atrophy an infectious disease? Ann Neurol 83:10-12
Kattah, Andrea G; Smith, Carin Y; Gazzuola Rocca, Liliana et al. (2018) CKD in Patients with Bilateral Oophorectomy. Clin J Am Soc Nephrol 13:1649-1658
Khosla, Sundeep; Monroe, David G (2018) Regulation of Bone Metabolism by Sex Steroids. Cold Spring Harb Perspect Med 8:

Showing the most recent 10 out of 401 publications