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: 9038313
• 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 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9038313
• 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; 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（由申请方提供）：哺乳引起母体钙和骨代谢的实质性变化，因为母体骨骼是乳汁生产中钙的主要来源。在哺乳期，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著特点是，断奶后骨量和结构迅速恢复。控制从泌乳期间的净吸收到断奶后的净形成的转换的机制尚不清楚。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）抑制骨吸收和骨形成，因此不能以哺乳期妇女断奶后发生的方式恢复恶化的骨骼。在哺乳期间，PTH相关蛋白（PTHrP）从乳腺分泌到血流中。PTHrP循环水平的增加有助于哺乳期间骨吸收和骨丢失速率的增加。然而，PTHrP介导哺乳后骨恢复的内分泌功能尚不清楚。最近的一项研究表明，停止7天的PTHrP输注引起骨形成活动的突然反弹。鉴于事实上，血浆PTHrP水平迅速下降后哺乳期，我们推测，这种变化在循环PTHrP发挥了重要作用，刺激哺乳后骨形成。本研究的总体目标是确定雌激素和循环PTHrP在哺乳后显著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，通过使用体内CT成像和个体骨小梁动力学分析，将阐明在断奶过程中替换断开的骨小梁杆和穿孔的骨小梁板的独特结构恢复机制，并将这些恢复机制与给予ERT的卵巢切除（OVX）大鼠的恢复机制进行对比。在目的2中，通过在OVX模型中模拟泌乳诱导的PTHrP和雌激素水平的波动，并通过防止泌乳后大鼠在断奶时通常发生的PTHrP下降，来阐明断奶时PTHrP水平下降的作用。本研究的结果将促进我们对哺乳后骨恢复的系统调节的理解。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靶向骨形成的研究。