Bone structure and strength recovery and the role of PTHrP post lactation

哺乳后骨结构和力量恢复以及 PTHrP 的作用

• 批准号: 8704520
• 负责人: Xiaowei Sherry Liu
• 金额: $ 8万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704520
• 关键词: Accounting; Biomechanics; Blood; Bone Resorption; Calcitonin; Calcium; Continuous Infusion; Data; Drops; Endocrine; Estrogen Replacement Therapy; Estrogens; Finite Element Analysis; Gene Expression; Goals; Health; Hormones; Image; Individual; Infusion procedures; Investigation; Lactation; Mammary gland; Mechanics; Mediating; Milk; Modeling; Morphology; Mothers; Mus; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Physiological; Plasma; Play; Postmenopausal Osteoporosis; Postmenopause; Process; Production; Property; Proteins; Rattus; Recovery; Regulation; Role; Serum; Signal Transduction; Simulate; Skeleton; Source; Stream; Structure; Synchrotrons; Techniques; Therapeutic; Vitamin D; Weaning; Woman; X-Ray Computed Tomography; base; bone; bone loss; bone mass; bone metabolism; bone strength; bone turnover; calcium metabolism; falls; in vivo; insight; nano; prevent; repaired; retinal rods

DESCRIPTION (provided by applicant): Lactation induces substantial changes in maternal calcium and bone metabolism, as the mother's skeleton serves as a major source of calcium in milk production. During lactation, there is a dramatic decline in bone mass and microstructure similar to postmenopausal bone loss, as both phenomena are associated with reduced estrogen levels and increased bone turnover. What is remarkable about lactation-induced bone loss is that bone mass and structure are rapidly restored after weaning. The mechanism that controls the switch from net resorption during lactation to net formation after weaning is not well understood. It has been postulated that the increase in estrogen levels after lactation contributes to bone recovery. However, when used to treat post- menopausal osteoporosis, estrogen replacement therapy (ERT) suppresses both bone resorption and formation, and thus does not restore the deteriorated skeleton in the manner that occurs in lactating women after weaning. During lactation, PTH-related protein (PTHrP) is secreted from the mammary gland into the blood stream. The increased circulating level of PTHrP contributes to the increased rate of bone resorption and bone loss during lactation. However, the endocrine function of PTHrP on mediating post-lactation bone recovery is unclear. A recent study showed that cessation of a 7-day infusion of PTHrP caused an abrupt rebound of bone formation activities. Given the fact that plasma PTHrP levels rapidly decrease post-lactation, we hypothesize that this change in circulating PTHrP plays an important role in stimulating post-lactation bone formation. The overall goal of this study is to define the role of estrogen and circulating PTHrP in the remarkable bone structure and strength recovery after lactation, which may provide new insights into therapeutic strategies for recovering the lost structural integrity associated with postmenopausal osteoporosis. In Aim 1, unique structural recovery mechanisms of replacing disconnected trabecular rods and perforated trabecular plates during weaning will be elucidated by using in vivo CT imaging and individual trabecular dynamics analysis, and these recovery mechanisms will be contrasted with those of ovariectomized (OVX) rats given ERT. In Aim 2, the role of the drop in PTHrP levels at weaning will be elucidated by simulating lactation- induced fluctuations in PTHrP and estrogen levels in an OVX model, and by preventing the drop in PTHrP that normally takes place at weaning in post-lactation rats. Results of this study will advance our understanding of systematic regulation of post-lactation bone recovery. These data will also drive our investigations of targeted bone formation by defining local signals that trigge the repair of structural deficits.

描述（由申请人提供）：哺乳期会导致母体钙和骨代谢发生显着变化，因为母体骨骼是产奶过程中钙的主要来源。在哺乳期间，骨量和微观结构急剧下降，类似于绝经后骨质流失，因为这两种现象都与雌激素水平降低和骨转换增加有关。哺乳引起的骨质流失的显着之处在于断奶后骨质和结构迅速恢复。控制从哺乳期间的净吸收到断奶后的净形成的转变的机制尚不清楚。据推测，哺乳后雌激素水平的增加有助于骨骼恢复。然而，当用于治疗绝经后骨质疏松症时，雌激素替代疗法（ERT）会抑制骨吸收和形成，因此不会像断奶后哺乳期妇女那样恢复恶化的骨骼。哺乳期间，PTH 相关蛋白 (PTHrP) 从乳腺分泌到血流中。 PTHrP 循环水平的增加导致哺乳期间骨吸收和骨丢失的速度增加。然而，PTHrP 在介导哺乳后骨恢复中的内分泌功能尚不清楚。最近的一项研究表明，停止输注 7 天的 PTHrP 会导致骨形成活动突然反弹。鉴于血浆 PTHrP 水平在哺乳后迅速降低，我们假设循环 PTHrP 的这种变化在刺激哺乳后骨形成中发挥重要作用。本研究的总体目标是明确雌激素和循环 PTHrP 在哺乳后显着的骨结构和强度恢复中的作用，这可能为恢复与绝经后骨质疏松症相关的失去的结构完整性的治疗策略提供新的见解。在目标 1 中，将通过使用体内 CT 成像和个体小梁动力学分析来阐明断奶期间更换断开的小梁棒和穿孔小梁板的独特结构恢复机制，并将这些恢复机制与接受 ERT 的卵巢切除 (OVX) 大鼠的恢复机制进行对比。在目标 2 中，将通过在 OVX 模型中模拟哺乳引起的 PTHrP 和雌激素水平波动，并通过防止哺乳后大鼠断奶时通常发生的 PTHrP 下降来阐明断奶时 PTHrP 水平下降的作用。这项研究的结果将增进我们对哺乳后骨恢复系统调节的理解。这些数据还将通过定义触发结构缺陷修复的局部信号来推动我们对目标骨形成的研究。