Osteoporosis is a major public health problem, with over 50% of Caucasian women and nearly 20% of Caucasian men at risk for an osteoporotic fracture in their lifetime (NIH Osteoporosis and Related Bone Diseases - National Resource Center). While some of the predictors of peak bone mass (PBM) include genetic predisposition and environmental factors, such as physical activity and diet, peak bone mass is also influenced by rapid changes in reproductive hormone levels for both genders, especially estrogen and progesterone during the accelerated growth period. Despite its well-studied effects in the reproductive system, progesterone's effects on bone metabolism remain largely unknown. In our laboratory, mice whose nuclear progesterone receptors (PR) were rendered nonfunctional (PRKO) exhibited a rapid gain of bone mass (age 1-3 months) and greater peak bone mass but with a sex difference in magnitude of increase (3- fold higher PBM in females and +50% in males) in comparison to their wild type (WT) litter mates (Yao et al. 2009). Thus, the presence of progesterone nuclear receptors exerts inhibitory effects on bone formation during the period of rapid bone acquisition, and this inhibition is more profound in female mice. Based on our preliminary observations, we hypothesize that progesterone signaling inhibits bone formation during the rapid bone growth period such that peak bone mass is lower in females than in males. We further hypothesize that inhibition of progesterone signaling in osteoblasts during the period of rapid bone acquisition period accelerates achievement of peak bone mass, especially for females. To test our hypotheses, we propose the following specific aims:
Specific Aim 1 : To investigate the direct effects of PR deletion on osteoblast and bone formation and compare these effects in female and male mice.
Specific Aim 2 : To determine if the inhibition of PR in vivo will lead to an uncoupling of bone turnover, we will monitor bone architecture and bone turnover changes following these interventions to determine how these interventions affect peak bone mass acquisition and if the responses would be differ between the sexes.

Public Health Relevance

Osteoporosis is a major public health problem that currently affects 44 million Americans. Progesterone is known for its effects on the reproductive system, but its physiological roles in skeletal metabolism remains unclear. This study aims to clarify differences in peak bone mass acquisition between sexes with the overall goal of explaining sex differences in musculoskeletal diseases across the lifespan.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Specialized Center (P50)
Project #
3P50AR063043-05S1
Application #
9483804
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lester, Gayle E
Project Start
Project End
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
5
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of California Davis
Department
Type
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Zhong, Zhendong A; Kot, Alexander; Lay, Yu-An E et al. (2017) Sex-Dependent, Osteoblast Stage-Specific Effects of Progesterone Receptor on Bone Acquisition. J Bone Miner Res 32:1841-1852
Rogers, Tara S; Harrison, Stephanie; Swanson, Christine et al. (2017) Rest-activity circadian rhythms and bone mineral density in elderly men. Bone Rep 7:156-163
Kot, Alexander; Zhong, Zhendong A; Zhang, Hongliang et al. (2017) Sex dimorphic regulation of osteoprogenitor progesterone in bone stromal cells. J Mol Endocrinol 59:351-363
Zhang, Hongliang; Kot, Alexander; Lay, Yu-An E et al. (2017) Acceleration of Fracture Healing by Overexpression of Basic Fibroblast Growth Factor in the Mesenchymal Stromal Cells. Stem Cells Transl Med 6:1880-1893
Katzman, Wendy B; Huang, Mei-Hua; Kritz-Silverstein, Donna et al. (2017) Diffuse Idiopathic Skeletal Hyperostosis (DISH) and Impaired Physical Function: The Rancho Bernardo Study. J Am Geriatr Soc 65:1476-1481
Wise, B L; Niu, J; Guermazi, A et al. (2017) Magnetic resonance imaging lesions are more severe and cartilage T2 relaxation time measurements are higher in isolated lateral compartment radiographic knee osteoarthritis than in isolated medial compartment disease - data from the Osteoarthritis Initiat Osteoarthritis Cartilage 25:85-93
Tran, Tuan A; Williams, Lisa M; Bui, Donna et al. (2017) Prospective Pilot Study Comparing Pre- and Postsurgical CTSAQ and Neuro-QoL Questionnaire with Median Nerve High-Resolution Ultrasound Cross-Sectional Areas. J Hand Surg Am :
Rogers, Tara S; Blackwell, Terri L; Lane, Nancy E et al. (2017) Rest-activity patterns and falls and fractures in older men. Osteoporos Int 28:1313-1322
Manickam, Raj N; Mu, Yi; Kshirsagar, Abhijit V et al. (2017) Area-Level Poverty and Excess Hospital Readmission Ratios. Am J Med 130:e153-e155
Nielson, Carrie M; Wiedrick, Jack; Shen, Jian et al. (2017) Identification of Hip BMD Loss and Fracture Risk Markers Through Population-Based Serum Proteomics. J Bone Miner Res 32:1559-1567

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