RECOVERY OF BONE MASS AFTER LACTATION

描述（由申请人提供）：哺乳动物骨骼在繁殖过程中经历了一个显著的循环。哺乳期与大量骨的快速丢失有关，但这种缺陷在断奶后完全修复。事实上，哺乳期和随后的断奶后恢复期代表了成年骨骼中骨量损失和增加的最快速率。尽管如此，哺乳期骨质流失的调节机制仍只被部分理解，而刺激断奶后合成代谢反应的机制则一无所知。骨对哺乳的反应与其对绝经的反应之间有许多相似之处，并且已经表明绝经后骨质疏松症代表了旨在介导哺乳期骨丢失的机制的不适当的重新激活。如果这是真的，那么哺乳后骨量恢复的机制可能为绝经后骨质疏松症的治疗提供有价值的线索。然而，为了利用任何这样的线索，我们需要解决我们对哺乳后合成代谢反应性质的深刻无知。为了开始了解这一过程，我们提供了一个探索性的R21应用程序，旨在产生初步的数据，这将有助于进一步研究的机制，启动骨骼的反应断奶。我们的提案概述了三个具体目标。第一个是详细研究哺乳后骨量、骨转换、骨组织学和全身代谢的变化。第二部分将描述骨基因表达的变化，以确定可能介导这些变化的重要分子途径。最后，我们提供了初步的证据表明，典型的Wnt信号通路激活的骨细胞响应断奶。第三个目标将使用四环素调节的转基因系统来抑制哺乳后骨中的Wnt信号传导，以确定该信号传导途径是否有助于合成代谢反应的启动。

DESCRIPTION (provided by applicant): The mammalian skeleton undergoes a remarkable cycle of catabolism and anabolism during reproduction. Lactation is associated with rapid loss of a significant amount of bone, but this deficit is fully repaired after weaning. In fact, lactation and the subsequent recovery period post-weaning represent the most rapid rates of loss and gain in bone mass in the adult skeleton. Despite this fact, the mechanisms underlying the regulation of bone loss during lactation are only partly understood and nothing at all is know of the mechanisms that stimulate the anabolic response to weaning. There are many parallels between the response of bone to lactation and its response to menopause and it has been suggested that post- menopausal osteoporosis represents the inappropriate reactivation of mechanisms meant to mediate lactational bone loss. If this is true, then the mechanisms underlying the recovery of bone mass post- lactation may offer valuable clues for the treatment of post-menopausal osteoporosis. However, in order to capitalize on any such clues, we need to address our profound ignorance of the nature of the anabolic response after lactation. In order to begin to understand this process we offer an exploratory R21 application intended to generate preliminary data that will help to focus further studies on mechanisms that initiate the skeleton's response to weaning. Our proposal outlines three specific aims. The first entails studies meant to detail changes in bone mass, bone turnover, bone histology and systemic metabolism post-lactation. The second will profile changes in bone gene expression in order to identify important molecular pathways that might mediate these changes. Finally, we provide preliminary evidence to suggest that the canonical Wnt signaling pathway is activated in bone cells in response to weaning. The third aim will use a tetracycline- regulated transgenic system to inhibit Wnt signaling in bone after lactation in order to determine if this signaling pathway contributes to the initiation of the anabolic response.