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

描述(申请人提供)：哺乳期导致母亲钙和骨骼代谢的重大变化，因为母亲的骨骼是牛奶生产中钙的主要来源。在哺乳期间，骨量和微观结构会急剧下降，类似于绝经后的骨丢失，因为这两种现象都与雌激素水平降低和骨转换增加有关。哺乳期引起的骨丢失值得注意的是，断奶后骨量和结构迅速恢复。控制哺乳期间净吸收转变为断奶后净形成的机制尚不清楚。据推测，哺乳后雌激素水平的增加有助于骨骼的恢复。然而，当用于治疗绝经后骨质疏松症时，雌激素替代疗法(ERT)既抑制了骨吸收又抑制了骨形成，因此不能像哺乳期妇女断奶后那样恢复恶化的骨骼。在哺乳期，甲状旁腺激素相关蛋白(PTHrP)从乳腺分泌到血流中。血液中甲状旁腺素受体水平的升高导致了哺乳期骨吸收和骨丢失的增加。然而，甲状旁腺素受体在调节哺乳期后骨恢复中的内分泌作用尚不清楚。最近的一项研究表明，停止7天的PTHrP输注会导致骨形成活动的突然反弹。鉴于血浆PTHrP水平在哺乳期后迅速下降的事实，我们假设循环PTHrP的这种变化在刺激哺乳期后骨形成方面起着重要作用。本研究的总体目标是明确雌激素和循环PTHrP在哺乳期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相关的丢失的结构完整性的治疗策略提供新的见解。目的1通过活体CT成像和个体小梁动力学分析，阐明在断奶期间更换断连的小梁杆和穿孔的小梁板的独特结构恢复机制，并将这些恢复机制与卵巢切除(OVX)大鼠接受ERT的恢复机制进行对比。在目标2中，将通过在OVX模型中模拟哺乳期诱导的PTHrP和雌激素水平的波动，以及通过防止通常发生在哺乳期后大鼠断奶时的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期后骨恢复的系统调控的理解。这些数据还将通过定义触发结构性缺陷修复的局部信号来推动我们对靶向骨形成的研究。

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.