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）：繁殖与骨质流失和恢复的显着周期相关。新生儿的所有营养物质都依赖于牛奶，包括钙。为产奶提供足够的钙需要动员母亲体内的骨骼钙，而哺乳期是骨质快速流失的时期。断奶后，当产奶停止时，骨质会完全恢复，几乎与哺乳期间损失的速度一样快。我们之前的研究已经确定了哺乳期间乳房和骨骼之间以前未被认识到的反馈回路。哺乳会刺激乳房的传入神经，向下丘脑发出信号，抑制 GnRH 分泌并刺激催乳素释放。由此产生的低雌激素水平反过来会加速骨吸收并导致骨质流失。此外，哺乳期乳房将 PTHrP 分泌到体循环和乳汁中。我们的数据表明，循环 PTHrP 也有助于增加破骨细胞骨吸收和骨质流失。在哺乳期间，骨骼钙被动员用于产奶。因此，有趣的是，乳房表达钙敏感受体（CaR），并成为钙敏感器官，根据细胞外钙浓度的变化调节 PTHrP 分泌和钙转运。我们相信，这使得哺乳期乳腺能够监测其钙的供应，并相应地调整其钙的利用和骨骼钙的释放。如果输送到乳腺的钙量下降，则输送到乳汁中的钙量就会减少，并且会分泌更多的 PTHrP，以增加骨骼钙的输送量。当膳食钙供应有限时，这种反馈回路对于保护母亲免受低钙血症尤其重要。我们还提供的数据表明，断奶后的一波破骨细胞凋亡会导致骨吸收突然受到抑制，并触发哺乳后的骨骼恢复。我们延长这笔资助的目标是研究雌激素撤退和 PTHrP 过量在骨骼水平上相互作用导致哺乳期间骨吸收和骨质流失增加的机制。我们还将探讨雌激素水平的相互增加和 PTHrP 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 可能对新生儿骨代谢产生影响。由于乳汁中的 PTHrP 水平受乳腺钙可用性的调节，因此我们推测乳汁 PTHrP 水平的变化可能是协调母婴钙和骨代谢以对营养信号做出一致反应的一种机制。我们提出三个新的具体目标。第一个将测试 PTHrP 和雌激素戒断一起通过刺激 RANKL 信号传导起作用是否足以解释哺乳期间的所有骨质流失。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凋亡和骨吸收抑制，从而导致断奶后骨恢复。最终目标将利用遗传模型来确定牛奶 PTHrP 对新生儿骨骼和矿物质代谢的影响。