Progesterone Receptors Influence Peak Bones Mass

黄体酮受体影响峰值骨量

基本信息

批准号：
8734221
负责人：
Wei Yao
金额：
$ 0.63万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8734221
关键词：
20 year old Ablation Achievement Adult Affect Age Aging American Architecture Bone Diseases Bone Growth Caucasians Caucasoid Race Cells Diet Environmental Risk Factor Estrogens Exhibits Female Future Gender Genetic Predisposition to Disease Goals Growth Hormones Instruction Intervention Investigation Laboratory mice Lead Longevity Maintenance Mediating Metabolism Methods Monitor Mus Musculoskeletal Musculoskeletal Diseases Nuclear Nuclear Receptors Osteoblasts Osteoclasts Osteocytes Osteogenesis Osteoporosis Partner in relationship Phenotype Physical activity Physiological Principal Investigator Progesterone Progesterone Receptors Public Health Reproductive system Resources Risk Role Sex Characteristics Signal Transduction Skeletal Development System Technology Testing Tetracycline Control Tissues United States National Institutes of Health Wild Type Mouse Woman base bone bone mass bone metabolism bone turnover clinical application in vivo male men novel strategies osteoporosis with pathological fracture programs promoter receptor expression recombinase reproductive hormone response sex sexual dimorphism skeletal

项目摘要

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. RELEVANCE (See instructions): 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.

骨质疏松症是一个主要的公共卫生问题，有超过50％的高加索妇女和近20％高加索男性在其一生中有骨质疏松性骨折的风险（NIH骨质疏松症和相关骨骼疾病 - 国家资源中心）。虽然峰值骨骼质量（PBM）的一些预测因子包括遗传易感性和环境因素，例如体育活动和饮食，峰值骨骼质量也是受性别的生殖激素水平的快速变化，尤其是雌激素和孕酮在加速生长期。尽管在生殖方面具有良好的影响系统，孕激素对骨代谢的影响在很大程度上尚不清楚。在我们的实验室，老鼠核孕酮受体（PR）的非功能性（PRKO）表现出骨骼的快速增长质量（1-3个月）和更大的峰值骨骼质量，但增加的性别差异（3-- 与其野生型（WT）垃圾伴侣相比，女性的PBM较高，男性 +50％）（Yao等。 2009）。因此，孕酮核受体的存在对骨形成产生抑制作用在快速获取骨骼的时期，这种抑制作用在雌性小鼠中更为深刻。基于我们的初步观察，我们假设孕酮信号传导抑制了骨形成快速骨生长周期，使女性的峰值骨骼质量低于男性。我们进一步假设在快速骨时期抑制成骨细胞中孕酮信号传导采集期加速了峰值骨量的实现，尤其是对于女性而言。测试我们的假设，我们提出以下具体目的：特定目的1：研究PR缺失对成骨细胞和骨形成的直接影响以及比较这些在男性和雄性小鼠中的影响。特定目的2：确定PR在体内的抑制是否会导致骨转换的解偶联，我们在这些干预措施之后，将监视骨结构和骨转换的变化，以确定如何这些干预措施会影响峰值骨骼的习得，如果反应会有所不同性别。相关性（请参阅说明）：骨质疏松症是目前影响4400万美国人的主要公共卫生问题。孕酮是以其对生殖系统的影响而闻名，但其生理作用在骨骼代谢中仍然存在不清楚。这项研究旨在澄清性别之间的峰值骨质量获取的差异解释整个生命周期中肌肉骨骼疾病的性别差异的目标。