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）：繁殖与骨质流失和恢复的显着循环有关。新生儿依靠牛奶来获得包括钙在内的所有营养素。为牛奶产量提供足够的钙需要动员母亲的骨骼钙，而泌乳是快速骨质流失的时期。断奶后，当牛奶生产停止时，骨骼质量完全恢复，几乎与哺乳期间丢失一样快。我们先前的研究定义了哺乳期间乳房和骨骼之间先前未知的反馈回路。哺乳可刺激乳房中的传入神经，以信号下丘脑以抑制GNRH分泌并刺激催乳素释放。产生的低雌激素水平反过来加速骨吸收并导致骨质流失。此外，哺乳后的乳房将PTHRP分泌到系统性循环和牛奶中。我们的数据表明，循环PTHRP也有助于增加破骨骨吸收和骨质流失。在泌乳过程中，动员骨骼钙是为了产生牛奶的目的。因此，令人着迷的是，乳房表达钙感应受体（CAR），并成为钙敏感器官，该器官可根据细胞外钙浓度的变化来调整PTHRP分泌和钙转运。我们认为，这使哺乳动物腺可以监测其钙的供应，并相应地调整其钙利用率和骨骼钙的释放。如果钙递送到乳腺下降，则将钙较少地输送到牛奶中，而更多的PTHRP被分泌以增加骨骼钙的递送。当饮食中钙供应限制时，这种反馈回路对于保护母亲免受低钙血症可能特别重要。我们还提供了数据，表明断奶后的破骨细胞凋亡浪潮会突然抑制骨吸收，并在哺乳后触发骨骼恢复。我们在扩展该赠款的目标是检查雌激素戒断和PTHRP多余在骨骼水平相互作用以导致泌乳过程中骨吸收和骨质流失的机制。我们还将探索是否会伴随雌激素水平的相互增加和PTHRP水平下降可以抑制断奶时骨吸收的作用。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。由于牛奶中的PTHRP水平受乳腺的钙可用性调节，因此我们假设牛奶PTHRP水平的改变可能是母体和新生儿钙和骨代谢的一种机制，可以协同响应协同的营养线索。我们提供三个新的特定目标。第一个将测试PTHRP和雌激素戒断是否通过刺激RANKL信号传导起作用，足以解释泌乳过程中所有骨质流失。第二个将确定RANKL信号传导，雌激素水平和PTHRP浓度的改变是否有助于破骨细胞凋亡以及抑制骨吸收，从而导致断奶后骨骼恢复。最终目标将使用遗传模型来定义牛奶PTHRP对新生儿骨和矿物质代谢的影响。