Endocrine Actions of Sclerostin

硬化素的内分泌作用

• 批准号: 9898240
• 负责人: Ryan C Riddle
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898240
• 关键词: Acute; Address; Adipocytes; Adipose tissue; Aging; Award; Body Composition; Bone Diseases; Bone Matrix; Breeding; Cells; Communication; Consumption; Data; Dependovirus; Deposition; Development; Diabetes Mellitus; Diagnosis; Distant; Endocrine; Energy Metabolism; Energy Supply; Exhibits; Fatty acid glycerol esters; Genetic; Genetic Recombination; Glucose; Growth; High Fat Diet; Hormone secretion; Human; In Vitro; Ions; LDL-Receptor Related Protein 1; Lead; Lipids; Lipoprotein Receptor; Locomotion; Mediating; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Minerals; Modeling; Modification; Molecular; Mus; Obesity; Organ; Osteoblasts; Osteocytes; Osteogenesis; Osteopenia; Osteoporosis; Performance; Pharmacology; Physiologic calcification; Physiological; Play; Population; Prevalence; Prevention; Production; Regulation; Research Design; Series; Signal Transduction; Skeleton; Societies; Therapeutic; Time; Tissues; Transgenic Mice; Veterans; WNT Signaling Pathway; Wild Type Mouse; adipocyte differentiation; beta catenin; blood glucose regulation; bone; bone mass; cohort; fatty acid metabolism; glucose tolerance; human data; improved; in vivo; inhibitor/antagonist; insight; insulin sensitivity; lipoprotein receptor related protein 5; mutant; neutralizing antibody; novel; receptor; therapeutic target; tissue repair

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.

骨骼由大量成骨细胞和骨细胞填充，需要持续的供应 能量富含能量的分子以燃料：骨基质的合成，沉积和矿化 建模和重塑。结果，在过去十年中进行的研究扩大了我们 了解超出运动，矿物离子储存和骨骼的生理功能 现在保护重要器官，包括促进调节的激素的分泌 全身代谢。硬化蛋白，一种骨细胞分泌因子，抑制Wnt信号传导 与低密度脂蛋白受体相关蛋白5（LRP5）和LRP6共受体相互作用，具有 通常被视为骨形成的局部抑制剂。但是，人类数据提高了 硬化蛋白还可以拮抗遥远组织中的Wnt信号作为循环水平的可能性是 代谢功能障碍的条件增加。此外，在此描述的初步研究 提案表明硬化症缺乏症（SOST - / - 小鼠）改变了身体成分和葡萄糖 稳态，这种硬化症治疗增加了脂肪细胞的分化。这些数据导致我们进入 假设硬化蛋白实现了一个内分泌功能，使骨骼可以与其他 代谢活性组织，并有助于全身代谢的协调。 在此应用中，我们将利用遗传和药理方法的组合来探索 硬化素对脂肪组织发育和功能的影响。我们的假设预测 循环硬化素通过抑制Wnt共同的信号传导来增强脂肪的积累 受体LRP5，并且该功能由假定的硬化蛋白受体LRP4促进。我们的方法 将使硬化蛋白的先前意外功能鉴定。我们坚信 从我们的研究中获得的信息将提高人们对如何代谢活动的理解 骨骼影响全球代谢活性。这些信息有望显着改善 诊断，管理，治疗和预防糖尿病相关代谢疾病 和老年退伍军人的骨病。