Effects of reproduction and lactation on postmenopausal bone health.

项目摘要 女性骨骼在生殖过程中会发生巨大的生理变化。而 断奶诱导大量的骨恢复，生殖诱导的骨丢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，生殖和哺乳史没有 消极的，甚至是对以后生活中骨折风险的保护作用。这代表了一个悖论， 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，尽管较低的 骨量，生殖大鼠具有独特的骨结构表型和骨丢失速度慢得多 与未孕大鼠相比，卵巢切除术（OVX）导致雌激素缺乏。OVX后3个月， 在生殖过程中，支承部位，如椎体松质骨和股骨中段，没有显示出骨丢失。 大鼠我们的数据还表明，骨细胞可以主动调节陷窝周围骨的材料特性 在繁殖过程中，这可能导致微机械环境的重大改变， 骨细胞，骨中假定的机械传感器。事实上，我们的研究结果表明， 对体内胫骨载荷的敏感性高于未孕大鼠。此外，当在以后的生活中遭受OVX时， 生殖期大鼠骨细胞陷窝明显增大。微环境的变化 生殖后的骨骼损伤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、中心的研究提供了强有力的科学前提。 假设生殖和哺乳史导致骨骼在结构、材料和 细胞水平，这可能会保护骨骼从雌激素缺乏引起的骨质流失以后的生活。测试 为了确定这一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、细胞学和免疫反应影响 活动，以及在以后的生活中对雌激素缺乏的机械敏感性。在目标2中，我们将确立 调节腔隙和小管结构、腔隙周围骨组织模量的生殖史，以及 OVX前和OVX后大鼠骨细胞及其过程所经历的负荷诱导的液体流动。我们 将解决一个悬而未决的临床悖论，并阐明保护妇女的惊人的适应机制， 有绝经后骨质疏松症的妊娠和哺乳史。识别表型骨 原始骨和生殖骨的结构、材料特性和骨细胞微环境可能导致 预防、管理和治疗绝经后妇女骨质疏松症的新策略， 考虑到它们的繁殖历史这项极具影响力的研究也将推动我们的基础研究。 了解骨细胞骨陷窝周围重塑及其对骨力学敏感性的调节。

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.