Endocrine Actions of Sclerostin

骨骼由大量的成骨细胞和骨细胞组成，需要持续的 富含能量的分子，为骨形成过程中骨基质的合成、沉积和矿化提供能量 建模和改造。因此，在过去十年中进行的研究扩大了我们的 了解骨骼运动以外的生理功能，矿物离子储存， 保护重要器官，现在包括分泌有助于调节 全身代谢硬化蛋白，一种骨细胞分泌的因子，通过抑制Wnt信号传导， 与低密度脂蛋白受体相关蛋白5（Lrp 5）和Lrp 6共受体相互作用， 通常被视为骨形成的局部抑制剂。然而，人类数据提高了 硬化蛋白也可能拮抗远端组织中的Wnt信号传导，因为循环水平是 在代谢功能障碍的情况下增加。此外，本文所述的初步研究 一项提案表明硬化蛋白缺乏（Sost-/-小鼠）改变了身体组成和葡萄糖 稳态，且硬化蛋白处理增强脂肪细胞分化。这些数据使我们 假设硬骨素具有内分泌功能， 代谢活性组织，并有助于协调全身代谢。 在本申请中，我们将利用遗传学和药理学方法的组合来探索 硬化蛋白对脂肪组织发育和功能的影响。我们的假设预测， 循环硬化蛋白通过抑制Wnt共刺激下游信号传导增强脂肪积累， 受体Lrp 5，并且该功能由Lrp 4（一种假定的硬化素受体）促进。我们的方法 将能够鉴定硬化蛋白以前未预料到的功能。我们坚信 从我们的研究中获得的信息将提高对代谢活动的理解， 骨骼影响整体代谢活动。这些信息预计将大大改善 糖尿病相关代谢紊乱的诊断、管理、治疗和预防 老年退伍军人的骨骼疾病

The skeleton, populated by large numbers of osteoblasts and osteocytes, requires a constant supply of energy-rich molecules to fuel the: synthesis, deposition, and mineralization of bone matrix during bone modeling and remodeling. As a result, studies performed over the last decade have expanded our understanding of the physiologic functions of bone beyond locomotion, mineral ion storage, and protection of vital organs to now include the secretion of hormones that contribute to the regulation of whole-body metabolism. Sclerostin, an osteocyte-secreted factor that inhibits Wnt signaling by interacting with the low-density lipoprotein receptor-related protein 5 (Lrp5) and Lrp6 co-receptors, has generally been viewed as a local inhibitor of bone formation. However, human data raises the possibility that sclerostin also antagonizes Wnt signaling in distant tissues as circulating levels are increased in conditions of metabolic dysfunction. Moreover, preliminary studies described in this proposal demonstrate that sclerostin deficiency (Sost-/- mice) alters body composition and glucose homeostasis, and that sclerostin treatment augments adipocyte differentiation. These data lead us to hypothesize that sclerostin fulfills an endocrine function that allows bone to communicate with other metabolically active tissues, and to contribute to the coordination of whole body metabolism. In this application, we will utilize a combination of genetic and pharmacological approaches to explore the impact of sclerostin on adipose tissue development and function. Our hypothesis predicts that circulating sclerostin enhances fat accumulation by suppressing signaling downstream of the Wnt co- receptor Lrp5 and that this function is facilitated by Lrp4, a putative sclerostin receptor. Our approach will enable the identification of previously unanticipated functions of sclerostin. We firmly believe that the information gained from our studies will improve understanding of how the metabolic activity of the skeleton impacts global metabolic activity. Such information is expected to significantly improve the diagnosis, management, treatment, and prevention of the related metabolic disturbances of diabetes and bone disease in aging Veterans.