THE EFFECT OF PTHrP DURING LACTATION

PTHrP 对哺乳期的影响

• 批准号: 7370140
• 负责人: John J Wysolmerski
• 金额: $ 32.65万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7370140
• 关键词: Apoptosis; Blood Circulation; Bone Growth; Bone Resorption; Bone Resorption Inhibition; Breast; Calcium; Calcium Milk; Calcium-Sensing Receptors; Cues; Data; Dietary Calcium; Discipline of Nursing; Estrogens; Feedback; Genes; Genetic Models; Gland; Goals; Grant; Homeostasis; Hormones; Hypocalcemia result; Hypogonadism; Hypothalamic structure; Inhibition of Apoptosis; Laboratories; Lactation; Mammary gland; Metabolism; Milk; Minerals; Monitor; Mothers; Mus; Neonatal; Newborn Infant; Nutrient; Nutritional; Osteoclasts; Osteoporosis; Postmenopausal Osteoporosis; Production; Prolactin; Prolonged Lactations; Protein Secretion; Purpose; Recovery; Reproduction; Sense Organs; Signal Pathway; Signal Transduction; Skeletal system; Skeleton; Source; TNFSF11 gene; Testing; Weaning; Withdrawal; afferent nerve; bone; bone loss; bone metabolism; bone turnover; extracellular; falls; neonate; novel therapeutics; parathyroid hormone-related protein; pup; repaired; response

DESCRIPTION (provided by applicant): Reproduction is associated with a remarkable cycle of bone loss and recovery. Newborns depend on milk for all nutrients, including calcium. Supplying enough calcium for milk production requires the mobilization of skeletal calcium in the mother, and lactation is a period of rapid bone loss. After weaning, when milk production ceases, bone mass recovers completely, almost as rapidly as it was lost during lactation. Our prior studies have defined a previously unrecognized feedback loop between breast and bone during lactation. Suckling stimulates afferent nerves in the breast to signal the hypothalamus to inhibit GnRH secretion and stimulate prolactin release. The resulting low estrogen levels, in turn, accelerate bone resorption and cause bone loss. In addition, the lactating breast secretes PTHrP into the systemic circulation and milk. Our data demonstrate that circulating PTHrP also contributes to increased osteoclastic bone resorption and bone loss. During lactation, skeletal calcium is mobilized for the purposes of milk production. Therefore, it is intriguing that the breast expresses the calcium-sensing receptor (CaR) and becomes a calcium-sensing organ that adjusts both PTHrP secretion and calcium transport in response to changes in the extracellular calcium concentration. We believe that this allows the lactating mammary gland to monitor its supply of calcium and to adjust its calcium utilization and skeletal calcium release accordingly. If calcium delivery to the mammary gland falls, less calcium is transported into milk and more PTHrP is secreted to increase delivery of skeletal calcium. This feedback loop may be particularly important to protect the mother from hypocalcemia when dietary calcium supplies are limiting. We also present data suggesting that a wave of osteoclast apoptosis just after weaning leads to a sudden inhibition of bone resorption and triggers skeletal recovery after lactation. Our goal in the extension of this grant is to examine the mechanisms by which estrogen withdrawal and PTHrP excess interact at a skeletal level to cause an increase in bone resorption and bone loss during lactation. We will also explore if a reciprocal increase in estrogen levels and fall in PTHrP levels may act to inhibit bone resorption at weaning. Finally, our data suggest that the PTHrP found in milk may exert effects on neonatal bone metabolism. Because PTHrP levels in milk are regulated by calcium availability to the mammary gland, we hypothesize that alterations in milk PTHrP levels may be a mechanism by which maternal and neonatal calcium and bone metabolism are coordinated to respond to nutritional cues in concert. We offer three new specific aims. The first will test if PTHrP and estrogen withdrawal together, acting through stimulation of RANKL signaling, are sufficient to explain all bone loss during lactation. The second will determine if alterations in RANKL signaling, estrogen levels and PTHrP concentrations contribute to osteoclast apoptosis and the inhibition of bone resorption that leads to bone recovery after weaning. The final aim will use genetic models to define the effects of milk PTHrP on neonatal bone and mineral metabolism.

描述(由申请人提供)：生殖与骨丢失和骨恢复的显著周期有关。新生儿所有的营养都依赖于牛奶，包括钙。为牛奶生产提供足够的钙需要动员母亲体内的骨骼钙，而哺乳期是骨骼迅速流失的时期。断奶后，当停止产奶时，骨量会完全恢复，几乎与哺乳期间失去的骨量一样快。我们之前的研究已经定义了哺乳期乳房和骨骼之间的一个以前未被发现的反馈回路。吮吸刺激乳房中的传入神经，向下丘脑发出信号，抑制GnRH的分泌，刺激催乳素的释放。由此产生的低雌激素水平，反过来又会加速骨吸收，导致骨丢失。此外，哺乳期的乳房会将甲状旁腺素分泌到体循环和乳汁中。我们的数据表明，循环中的甲状旁腺素受体也有助于增加破骨细胞性骨吸收和骨丢失。在哺乳期间，骨骼钙被动员起来用于产奶。因此，有趣的是，乳房表达钙敏感受体(CAR)，并成为钙敏感器官，调节PTHrP的分泌和钙的运输，以响应细胞外钙浓度的变化。我们认为，这使得哺乳期乳腺可以监测其钙的供应，并相应地调整其钙利用和骨骼钙的释放。如果向乳腺输送的钙减少，进入乳汁的钙就会减少，而分泌更多甲状旁腺素的甲状旁腺素就会增加骨骼钙的输送。当饮食钙供应有限时，这种反馈回路对于保护母亲免受低钙血症的影响可能特别重要。我们还提供的数据表明，断奶后的破骨细胞凋亡浪潮会导致骨吸收的突然抑制，并在哺乳后触发骨骼恢复。我们延长这项资助的目的是研究雌激素退出和甲状旁腺素释放过多在骨骼水平上相互作用，导致哺乳期骨吸收和骨丢失增加的机制。我们还将探索雌激素水平的对等增加和甲状旁腺素受体水平的下降是否可能抑制断奶时的骨吸收。最后，我们的数据表明，牛奶中发现的PTHrP可能对新生儿的骨代谢产生影响。由于牛奶中的PTHrP水平受乳腺中钙供应的调节，我们推测，牛奶中PTHrP水平的变化可能是母体和新生儿的钙和骨代谢协调的一种机制，以协调对营养提示的反应。我们提出了三个新的具体目标。第一个将测试PTHrP和雌激素撤除一起，通过刺激RANKL信号起作用，是否足以解释哺乳期间的所有骨丢失。第二个将确定RANKL信号、雌激素水平和PTHrP浓度的变化是否有助于破骨细胞的凋亡和骨吸收的抑制，从而导致断奶后的骨恢复。最终目标将使用遗传模型来确定牛奶甲状旁腺素对新生儿骨骼和矿物质代谢的影响。