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 女性骨骼由于繁殖而经历了戏剧性的生理改变。尽管 断奶可引起大量的骨恢复，仅在 断奶。然而，大多数流行病学研究报告说，繁殖和泌乳的史没有 消极，甚至对骨折风险后期的保护作用。这代表了繁殖的悖论 减少骨骼质量而不会增加未来骨折的风险。因此，这项研究的总体目标是 发现解释这种悖论的机制。我们的初步结果表明，尽管较低 骨骼质量，生殖大鼠具有独特的骨结构表型，骨质流失速度较慢 当卵巢切除术（OVX）暴露于雌激素缺乏时，比处女大鼠。 OVX后3个月，负载 轴承位点，例如椎骨骨和股骨中部，没有骨质流失 老鼠。我们的数据还表明，骨细胞可以主动调节乳牙周围骨的材料特性 复制过程中的矩阵，这可能导致在微机械环境中的重大改变 骨细胞，骨骼中推测的机械传感器。实际上，我们的结果表明，生殖后大鼠 比处女大鼠对体内胫骨负荷更敏感。另外，当生活后来受到OVX的束缚时 生殖大鼠的骨细胞间隙的大小显着增加。因此，微环境变化 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骼质量。 这些来自临床和动物研究的发现为我们的小说中心提供了强大的科学前提 假设繁殖和泌乳病史会导致结构，物质和 细胞水平可以保护骨骼免受雌激素缺乏引起的骨骼流失。测试 该假设并确定其背后的机制，我们提出了两个目标。在AIM 1中，我们将确定 繁殖和泌乳历史对骨微结构，细胞中骨骼反应的影响 活动和机械敏感性对雌激素缺乏症的生命后期。在AIM 2中，我们将确定 在调节lacunar和管道结构，lacunar骨组织模量以及 骨细胞及其过程在先前和后的大鼠中都经历了负荷诱导的液体。我们 将解决未解决的临床悖论，并阐明保护女性的惊人适应机制 具有绝经后骨质疏松症的怀孕和泌乳病史。识别表型骨 处女中的结构，材料特性和骨细胞微环境和生殖骨可能会导致 通过 考虑他们的繁殖历史。这项高度影响力的研究也将推动我们的基本 了解骨细胞乳清乳清重塑及其对骨骼敏感性的调节。