THE EFFECT OF PTHrP DURING LACTATION

PTHrP 对哺乳期的影响

• 批准号: 7666650
• 负责人: John J Wysolmerski
• 金额: $ 32.08万
• 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/7666650
• 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; Recovery; Reproduction; Sense Organs; Signal Pathway; Signal Transduction; Skeleton; Source; TNFSF11 gene; Testing; Weaning; Withdrawal; afferent nerve; bone; bone loss; bone mass; bone metabolism; bone turnover; extracellular; falls; neonate; novel therapeutics; parathyroid hormone-related protein; pup; repaired; response; skeletal; treatment strategy

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）：生殖与骨质流失和恢复的显著周期有关。新生儿依靠牛奶获取包括钙在内的所有营养。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，骨量完全恢复，几乎和哺乳期一样快。我们之前的研究已经定义了哺乳期间乳房和骨骼之间以前未被认识到的反馈回路。哺乳刺激乳房内的传入神经，向下丘脑发出信号，抑制GnRH分泌，刺激催乳素释放。由此导致的低雌激素水平，反过来，加速骨吸收，导致骨质流失。此外，哺乳期的乳房分泌PTHrP进入体循环和乳汁。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，骨骼钙被动员起来用于产奶。因此，令人感兴趣的是，乳房表达钙感应受体（CaR）并成为钙感应器官，根据细胞外钙浓度的变化调节PTHrP分泌和钙转运。我们认为，这使泌乳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。如果钙输送到乳腺下降，更少的钙被输送到乳汁中，更多的PTHrP被分泌，以增加骨骼钙的输送。当饮食中的钙供应受到限制时，这种反馈循环可能对保护母亲免受低钙血症的影响尤为重要。我们也提供了数据表明，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。我们的目标是研究雌激素停药和PTHrP过量在骨骼水平上相互作用导致哺乳期骨吸收增加和骨质流失的机制。我们还将探讨是否雌激素水平的相互增加和PTHrP水平的下降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有影响。由于乳汁中的PTHrP水平受乳腺钙供应的调节，我们假设乳汁中PTHrP水平的改变可能是一种机制，通过这种机制，母体和新生儿的钙和骨代谢协调一致，以对营养线索做出反应。我们提出了三个新的具体目标。第一项试验将测试PTHrP和雌激素的退出是否通过刺激RANKL信号共同作用，足以解释哺乳期所有的骨质流失。第二项研究将确定RANKL信号、雌激素水平和PTHrP浓度的改变是否有助于破骨细胞凋亡和抑制骨吸收，从而导致断奶后骨恢复。最终目的是利用遗传模型来确定牛奶中PTHrP对新生儿骨骼和矿物质代谢的影响。