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: 9923534
• 负责人: Xiaowei Sherry Liu
• 金额: $ 34.13万
• 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/9923534
• 关键词: Address; Affect; Amaze; Animals; Attenuated; Bone Density; Bone Matrix; Bone Resorption; Bone Tissue; Bone structure; Clinical; Data; Environment; Estrogens; Exposure to; 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.

项目概要 由于繁殖，女性骨骼经历了巨大的生理变化。尽管 断奶导致骨质大量恢复，繁殖引起的骨质流失在断奶后仅部分恢复 断奶。然而，大多数流行病学研究报告称，生殖和哺乳史没有影响。 消极的，甚至对以后生活中的骨折风险有保护作用。这代表了一个悖论：繁殖 减少骨量而不增加未来骨折的风险。因此，本研究的总体目标是 揭示解释这一悖论的机制。我们的初步结果表明，尽管较低 骨量方面，繁殖大鼠具有独特的骨结构表型，并且骨丢失速度要慢得多 与通过卵巢切除术（OVX）暴露于雌激素缺乏的处女大鼠相比。 OVX后3个月，负荷 椎骨小梁和股骨中轴等承载部位在生殖过程中没有显示骨质流失 老鼠。我们的数据还表明，骨细胞可以主动调节腔隙周围骨的材料特性 繁殖过程中的基质，这可能导致微机械环境发生重大变化 骨细胞，推测为骨骼中的机械传感器。事实上，我们的结果表明，繁殖后的大鼠 与原始大鼠相比，它们对体内胫骨负荷更敏感。此外，当在以后的生活中遭受 OVX 时， 繁殖大鼠中骨细胞腔隙的大小显着增加。因此，微环境发生变化 繁殖后可能会影响骨骼对机械刺激的敏感性，并影响以后生活中的骨质量。 这些来自临床和动物研究的发现为我们新颖的、中心的研究提供了强有力的科学前提。 假设生殖和哺乳的历史导致骨骼在结构、材料和功能上的适应 细胞水平，这可以保护骨骼免受晚年雌激素缺乏引起的骨质流失的影响。测试 对于这个假设并确定其背后的机制，我们提出了两个目标。在目标 1 中，我们将确定 生殖和哺乳史对骨微结构、细胞骨骼反应的影响 活动以及晚年对雌激素缺乏的机械敏感性。在目标 2 中，我们将确立以下角色： 调节腔隙和小管结构、腔隙周围骨组织模量的繁殖史，以及 OVX 之前和之后的大鼠中骨细胞及其过程经历的负载诱导的流体流动。我们 将解决一个未解决的临床悖论，并阐明保护女性的惊人的适应性机制 有绝经后骨质疏松症妊娠和哺乳史。识别表型骨 原始骨和再生骨的结构、材料特性和骨细胞微环境可能导致 绝经后妇女骨质疏松症预防、管理和治疗的新策略 考虑到它们的繁殖历史。这项极具影响力的研究也将推进我们的基础研究 了解骨细胞腔隙周围重塑及其对骨机械敏感性的调节。