THE EFFECT OF PTHrP DURING LACTATION

描述（由申请人提供）：生殖与骨丢失和恢复的显著周期相关。新生儿依靠牛奶获得所有的营养，包括钙。为牛奶生产提供足够的钙需要动员母亲的骨骼钙，而哺乳期是骨骼快速流失的时期。断奶后，当牛奶停止生产时，骨量完全恢复，几乎与哺乳期间丢失的速度一样快。我们之前的研究已经确定了哺乳期乳房和骨骼之间以前未被认识到的反馈回路。吮吸刺激乳房中的传入神经，向下丘脑发出信号，以抑制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，加速骨吸收，导致骨质流失。此外，哺乳期乳房分泌PTHrP进入体循环和乳汁。我们的数据表明，循环PTHrP也有助于增加骨细胞骨吸收和骨丢失。在哺乳期，骨骼钙被动员起来用于产奶。因此，有趣的是，乳腺表达钙敏感受体（CaR），并成为钙敏感器官，调节PTHrP分泌和钙转运，以响应细胞外钙浓度的变化。我们认为，这使得哺乳期乳腺能够监测其钙供应，并相应地调整其钙利用和骨骼钙释放。如果钙输送到乳腺福尔斯下降，则较少的钙被输送到乳汁中，并且更多的PTHrP被分泌以增加骨骼钙的输送。当膳食钙供应有限时，这种反馈回路对保护母亲免于低钙血症可能特别重要。我们还提出的数据表明，破骨细胞凋亡的浪潮后，断奶导致骨吸收的突然抑制，并触发骨骼恢复哺乳期后。我们的目标是在这个补助金的扩展是检查的机制，雌激素戒断和PTHrP过量在骨骼水平上相互作用，导致增加骨吸收和骨丢失在哺乳期。我们还将探讨雌激素水平的相互增加和PTHrP水平的下降是否可以抑制断奶时的骨吸收。最后，我们的数据表明，PTHrP在牛奶中发现可能对新生儿骨代谢产生影响。由于牛奶中的PTHrP水平是由乳腺的钙可用性调节的，我们假设牛奶PTHrP水平的改变可能是一种机制，通过这种机制，母亲和新生儿的钙和骨代谢协调一致，以响应营养提示。我们提出了三个新的具体目标。第一个将测试PTHrP和雌激素戒断是否通过RANKL信号刺激起作用，足以解释哺乳期间的所有骨丢失。第二项研究将确定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和抑制骨吸收，从而导致断奶后的骨恢复。最终的目标将使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。

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.