This is a competitive renewal application for P01 AG004875, """"""""Physiology of Bone Metabolism in an Aging Population."""""""" Osteoporosis is an enormous public health problem, and our overall goal is to better understand the mechanisms and consequences of bone loss with aging. As in the past, the major strength of our group is to bring together diverse disciplines into synergistic interactions, and the present application includes population-based epidemiology studies, intensive studies in the Clinical Research Unit (formerly the General Clinical Research Center), animal studies using novel mouse models, and basic cellular and molecular studies. Using this integrated approach, we propose to focus on three major areas: (1) Defining the mechanisms by which estrogen (E) regulates bone metabolism;(2) With increases in bone resorption, as in the setting of E deficiency, identifying the mechanisms by which osteoclasts regulate osteoblasts;and (3) Assessing the risk factors for and consequences of fractures that increase with E deficiency and with aging. Each of the Projects are aligned with one or more of these major themes: Project 1 (""""""""Pathophysiology of Osteoporosis"""""""") uses the human as the experimental model to address key, unresolved issues regarding E action on bone, including definitively establishing whether follicle-stimulating hormone modulates bone resorption in the setting of E deficiency and defining mechanisms for the age-related decrease in bone formation;Project 2 (""""""""Risk Factors for Fractures Among the Elderly"""""""") provides a population perspective on risk factors for fractures (""""""""secondary"""""""" osteoporosis) that exacerbate bone loss with E deficiency and with aging;Project 3 (""""""""Osteoclast Regulation of Bone Formation"""""""") pursues the basic biology and functional relevance of factors made by osteoclasts that regulate bone formation;and Project 4 (""""""""Estrogen Receptor Signaling Pathways in Bone"""""""") uses in vitro and novel mouse models to dissect E signaling pathways in bone. A single Core (""""""""Administrative and Biostatistics Core"""""""") provides the necessary infrastructure to support these Projects. Collectively, these studies strive to provide a comprehensive assesment of the pathogenesis and clinical impact of one of the most important disorders facing our aging population.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-8 (J2))
Program Officer
Sherman, Sherry
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mayo Clinic, Rochester
United States
Zip Code
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

Showing the most recent 10 out of 371 publications