Effects of reproduction and lactation on the functional spinal unit post menopause

项目摘要/摘要 哺乳期和更年期是矿物质和骨骼发生重大变化的生理事件 新陈代谢是由雌激素迅速下降的共同内分泌信号触发的，导致骨质流失。 因此，腰痛，特别是在生育期间和绝经后，通常与腰痛有关。 伴有腰椎间盘退行性变(IVDD)和椎骨骨质疏松。临床调查 表明产次对自我报告的LBP没有或负面影响，而最近的一项病例对照研究报告 母乳喂养是老年妇女临床诊断为IVDD的保护因素。因此，存在着一种 关于生殖和哺乳对FSU的影响的关键知识差距独立于 亲子关系的非生物效应。由于功能脊柱单位(FSU)由椎骨(VB)组成， 软骨终板(CEP)和椎间盘(IVD)，了解复制的交互影响 更年期对CEP和IVD动态平衡的影响对于揭示FSU的可能机制是必不可少的 改变以适应苛刻的新陈代谢条件。 我们的研究小组此前曾报道过怀孕期间和 哺乳后，断奶后迅速恢复。此外，哺乳史会起到保护作用。 VB防治绝经后骨质疏松症的研究尤其是胶管周围(PLC)的重塑活动 在有生殖史的大鼠去卵巢后显著增加，这可能会导致 溶质在腔隙-小管系统内的运输，以及随后改变的营养输送和 VB和CEP之间的运输可能影响IVD健康。因此，我们假设类似的先天基因 生殖补偿机制可能通过增强绝经后IVDD的 由于PLC重塑的增加，FSU内的局部营养物质的输送和运输。 这项建议的目的是建立和监测椎间盘的变化 FSU对雌激素缺乏的反应，并确定可能的机制 可以区分有和没有繁殖史的大鼠的反应。我们将(1)建立一个 确定生殖和哺乳对IVD组织生物学效应的动物模型并建立 通过调查生殖和更年期对IVD健康的交互影响，了解生殖和更年期之间的直接联系； (2)关注骨与CEP界面的局部溶质转运；(3)揭示骨细胞的新功能 调控营养物质跨IVD-CEP-VB功能单元转运的PLC重塑；(4)开发利用 成像方式(体内µCT和定量MRI T1和T2映射)，以跟踪结构的变化 IVD-CEP-VB功能单元，并检测IVD的溶质扩散系数。阐明细胞因子的生物学效应 FSU上的生殖和哺乳将为预防措施是否需要提供临床洞察力 考虑到绝经后妇女的地位以及生育和哺乳的历史，将其视为绝经后妇女。

Project Summary/Abstract Lactation and menopause are physiological events where substantial changes in mineral and skeletal metabolism are triggered by a shared endocrine signal of rapid estrogen decline, resulting in bone loss. Consequently, low back pain, particularly during childbearing and post menopause is commonly associated with intervertebral disc degeneration (IVDD) and osteoporosis of vertebral bone. Clinical investigations suggested that no or negative effect of parity on self-reported LBP while a recent case-control study reported breastfeeding as a protective factor for clinically diagnosed IVDD in elderly women. As a result, there exists a critical knowledge gap regarding the effects of reproduction and lactation on the FSU that are independent of non-biological effects of parenthood. As the functional spinal unit (FSU) consists of vertebral bone (VB), cartilage end plate (CEP), and intervertebral disc (IVD), understanding the interactive effects of reproduction and menopause on CEP and IVD homeostasis is essential to uncover possible mechanisms of how the FSU changes to accommodate demanding metabolic conditions. Our research group has previously reported significant vertebral bone loss during pregnancy and lactation followed by a rapid recovery post-weaning. Moreover, a history of lactation exerts a protective effect on VB against post-menopausal osteoporosis. In particular, perilacunar-canalicular (PLC) remodeling activities are significantly increased in rats with reproductive history post-OVX, which would likely lead to increased solute transport within the lacunar-canalicular system, and the subsequent altered nutrition delivery and transport between VB and CEP may impact IVD health. Therefore, we hypothesize that a similar innate compensatory mechanism from reproduction may protect against post-menopausal IVDD by enhancing the local nutrient delivery and transport within the FSU resulting from increased PLC remodeling. The objective of this proposal is to establish and monitor changes of intervertebral disc degeneration in the FSU in response to estrogen deficiency and identify possible mechanisms that may differentiate responses in rats with and without a reproduction history. We will (1) establish an animal model to determine the biological effect of reproduction and lactation on IVD tissue and establish a direct connection between reproduction and menopause by investigating their interactive effects on IVD health; (2) Focus on local solute transport at the bone and CEP interface; (3) Reveal novel functions of the osteocyte PLC remodeling in modulating nutrient transport across IVD-CEP-VB functional unit; (4) Develop and utilize imaging modalities (in vivo µCT and quantitative MRI T1 and T2 mapping) to track the structural changes of IVD-CEP-VB functional unit and examine solute diffusivity of the IVD. Elucidating the biological effects of reproduction and lactation on the FSU will provide clinical insight on whether preventative measures need to be taken for postmenopausal women by considering their status and history of reproduction and lactation.