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

项目总结/摘要 哺乳和绝经是生理事件，其中矿物质和骨骼的实质性变化 代谢是由共同的雌激素快速下降的内分泌信号触发的，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 椎间盘退变（IVDD）和椎体骨质疏松。临床研究 表明，产次对自我报告的LBP没有影响或有负面影响，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IVDD的保护因素。因此，存在一个 关于生殖和哺乳对FSU的影响的关键知识差距，这些影响独立于 父母身份的非生物学影响。由于脊柱功能单元（FSU）由椎骨（VB）组成， 软骨终板（CEP）和椎间盘（IVD），了解生殖的相互影响 和绝经对CEP和IVD内稳态的影响对于揭示FSU如何影响子宫内膜的可能机制是至关重要的。 改变以适应苛刻的代谢条件。 我们的研究小组以前曾报道过怀孕期间显著的椎骨骨质流失， 断奶后迅速恢复。此外，哺乳史具有保护作用 维生素B治疗绝经后骨质疏松症特别是，acunar-canalicular（PLC）重塑活动 在OVX后有生殖史的大鼠中显著增加，这可能导致增加 腔隙-小管系统内的溶质转运，以及随后改变的营养输送， VB和CEP之间的运输可能影响IVD健康。因此，我们假设， 来自生殖的代偿机制可能通过增强 局部营养输送和运输FSU内增加PLC重塑。 本提案的目的是建立和监测椎间盘的变化 在FSU的退化，以应对雌激素缺乏，并确定可能的机制， 可以区分有和没有生殖史的大鼠的反应。我们将（1）建立一个 动物模型，以确定生殖和哺乳对IVD组织的生物学效应，并建立 通过调查生殖和绝经对IVD健康的相互影响，了解它们之间的直接联系; (2)重点研究骨与CEP界面的局部溶质转运;（3）揭示骨细胞的新功能 PLC重构在调节营养物质跨IVD-CEP-VB功能单元转运中的作用;（4）开发和利用 成像模式（体内µCT和定量MRI T1和T2标测），以跟踪 IVD-CEP-VB功能单元，并检查IVD的溶质扩散率。阐明生物效应 FSU上的生殖和哺乳将提供关于预防措施是否需要 绝经后妇女应考虑其生殖和哺乳状况和历史。

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.