Effects of reproduction and lactation on postmenopausal bone health.

生殖和哺乳对绝经后骨骼健康的影响。

• 批准号: 9309401
• 负责人: Xiaowei Sherry Liu
• 金额: $ 35.15万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9309401
• 关键词: Address; Affect; Amaze; Animals; Attenuated; Bone Density; Bone Matrix; Bone Resorption; Bone Tissue; Bone structure; Clinical; Data; Environment; Estrogens; Female; Femur; Fracture; Future; Gene Expression; Human; Knowledge; Lactation; Lead; Life; Linear Regressions; Mechanical Stimulation; Mechanics; Modeling; Modulus; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Osteoporosis; Osteoporosis prevention; Ovariectomy; Pattern; Phenotype; Physiological; Postmenopausal Osteoporosis; Postmenopause; Pregnancy; Pregnancy Histories; Process; Property; Rattus; Recording of previous events; Recovery; Regulation; Reporting; Reproduction; Research; Resistance; Risk; Role; Series; Site; Skeleton; Stimulus; Structure; Testing; Thick; Time; Weaning; Weight-Bearing state; Woman; bone; bone cell; bone health; bone loss; bone mass; bone quality; child bearing; environmental change; epidemiology study; experience; fluid flow; fracture risk; improved; in vivo; innovation; insight; novel; novel strategies; protective effect; reproductive; response; sensor; skeletal; spine bone structure; substantia spongiosa

Project Summary The female skeleton undergoes dramatic physiological alterations as a result of reproduction. While weaning induces substantial bone recovery, reproduction-induced bone loss is only partially recovered after weaning. Nevertheless, most epidemiology studies report that history of reproduction and lactation had no negative, or even a protective effect on fracture risk later in life. This represents a paradox that reproduction reduces bone mass without increasing risk of future fractures. Thus, the overall objective of this study is to uncover the mechanisms that explain this paradox. Our preliminary results demonstrated that despite a lower bone mass, reproductive rats have a distinct bone structural phenotype and a much slower rate of bone loss than virgin rats when exposed to estrogen deficiency by ovariectomy (OVX). 3 months after OVX, the load bearing sites, such as vertebral trabecular bone and femoral midshaft, showed no bone loss in reproductive rats. Our data also indicated that osteocytes can actively modulate material properties of the peri-lacunar bone matrix during reproduction, which could lead to critical alterations in the micro-mechanical environment of osteocytes, the presumed mechano-sensors in bone. Indeed, our results suggested that post-reproductive rats were more sensitive to in vivo tibial loading than virgin rats. In addition, when subjected to OVX later in life, the size of osteocyte lacunae increased significantly in reproductive rats. Thus, the micro-environmental changes after reproduction may affect the skeleton's sensitivity to mechanical stimuli and impact bone quality later in life. These findings from clinical and animal studies provide a strong scientific premise for our novel, central hypothesis that history of reproduction and lactation causes skeletal adaptation at the structural, material, and cellular levels, which may protect the skeleton from estrogen deficiency-induced bone loss later in life. To test this hypothesis and determine the mechanisms behind it, we propose two aims. In Aim 1, we will determine the influence of reproduction and lactation history on skeletal responses in bone microarchitecture, cellular activities, and mechano-sensitivity to estrogen deficiency later in life. In Aim 2, we will establish the role of reproduction history on modulating lacunar and canalicular structure, peri-lacunar bone tissue modulus, and load-induced fluid flow experienced by osteocytes and their processes in both prior- and post-OVX rats. We will address an unsolved clinical paradox and elucidate the amazing adaptive mechanisms that protect women with a history of pregnancy and lactation from postmenopausal osteoporosis. Identifying the phenotypic bone structure, material properties, and osteocyte microenvironment in virgin and reproductive bone could lead to novel strategies for osteoporosis prevention, management, and treatment for postmenopausal women by considering their reproduction histories. This highly impactful research will also advance our fundamental understanding of osteocyte peri-lacunar remodeling and its regulation of bone's mechano-sensitivity.

项目摘要 由于繁殖，雌性骨骼经历了戏剧性的生理变化。而当 断奶后骨实质恢复，生殖引起的骨丢失仅部分恢复 断奶了。然而，大多数流行病学研究报告说，生殖和哺乳史没有 在以后的生活中，对骨折风险的负面影响，甚至是保护性作用。这代表了一种悖论，即繁殖 在不增加未来骨折风险的情况下减少骨量。因此，这项研究的总体目标是 揭示解释这一悖论的机制。我们的初步结果表明，尽管较低的 骨量，生殖大鼠有不同的骨结构表型，骨丢失速度要慢得多 比处女大鼠暴露于雌激素缺乏的卵巢切除(OVX)。OVX后3个月，负荷 承重部位，如椎体松质骨和股骨中段，在生殖功能方面没有骨丢失。 老鼠。我们的数据还表明，骨细胞可以积极地调节陷窝周围骨的材料特性。 在繁殖过程中，这可能会导致微机械环境的严重变化 骨细胞，被认为是骨骼中的机械传感器。事实上，我们的结果表明，生育后的大鼠 对体内胫骨负荷比未成年大鼠更敏感。此外，当在生命的后期接受OVX时， 生殖大鼠骨细胞陷窝明显增大。因此，微环境的变化 生殖后可能会影响骨骼对机械刺激的敏感性，并影响以后的骨骼质量。 这些来自临床和动物研究的发现为我们的新的、中央的 生殖和哺乳史导致骨骼结构、材料和组织适应的假设 细胞水平，这可能会保护骨骼免受雌激素缺乏导致的晚年骨丢失。为了测试 这一假说及其背后的机制，我们提出了两个目的。在目标1中，我们将确定 生殖和哺乳史对骨微结构、细胞内骨骼反应的影响 活动，以及对晚年雌激素缺乏的机械敏感性。在目标2中，我们将确立 调节骨陷窝和骨管结构、骨陷窝周围骨组织弹性的生殖史，以及 去卵巢前后大鼠骨细胞及其过程中所经历的负荷诱导的液体流动。我们 将解决一个尚未解决的临床悖论，并阐明保护女性的惊人适应机制 有绝经后骨质疏松症的妊娠和哺乳史。鉴定表型骨 处女骨和生殖骨的结构、材料特性和骨细胞微环境可能导致 绝经后妇女骨质疏松预防、管理和治疗的新策略 考虑到它们的繁殖史。这项极具影响力的研究也将推动我们的根本 了解骨细胞腔隙周围重塑及其对骨力学敏感性的调节。