Endocrine Actions of Sclerostin

骨骼由大量的成骨细胞和骨细胞组成，需要持续供应 能量丰富的分子促进骨基质的合成、沉积和矿化 造型和改建。因此，在过去十年中进行的研究扩大了我们的 了解骨骼的生理功能，超越运动、矿物质离子储存和 现在对重要器官的保护包括分泌有助于调节 全身新陈代谢。硬化素，一种骨细胞分泌因子，通过以下途径抑制Wnt信号 与低密度脂蛋白受体相关蛋白5(LRP5)和LRP6共受体相互作用，有 通常被认为是骨形成的局部抑制因子。然而，人类数据提高了 在远端组织中，随着循环水平的升高，硬化素也可能拮抗Wnt信号 代谢功能障碍的情况增加。此外，本文件中描述的初步研究 研究表明，硬化素缺乏(Sost-/-小鼠)会改变身体成分和血糖 动态平衡，而硬化素治疗促进脂肪细胞分化。这些数据让我们了解到 假设硬化素实现内分泌功能，允许骨骼与其他 代谢活跃的组织，并有助于协调全身新陈代谢。 在这个应用中，我们将利用遗传学和药理学的结合方法来探索 硬化素对脂肪组织发育和功能的影响。我们的假设预测 循环中的硬化素通过抑制Wnt联合信号转导途径促进脂肪堆积 LRP5受体，这一功能是由LRP4促进的，LRP4是一种可能的硬化素受体。我们的方法 将使以前没有预料到的硬化素功能的确定成为可能。我们坚信 从我们的研究中获得的信息将有助于我们更好地理解 骨骼影响全球新陈代谢活动。这些信息预计将显著改善 糖尿病相关代谢紊乱的诊断、管理、治疗和预防 以及老年退伍军人的骨病。

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.