Regulation of Osteoblast Metabolism by Lrp5

Lrp5 对成骨细胞代谢的调节

基本信息

批准号：
9049491
负责人：
Ryan C Riddle
金额：
$ 35.24万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-24 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9049491
关键词：
Ablation Address Alleles Animal Model Biochemical Biochemistry Biology Body Composition Bone Development Bone Tissue Characteristics Collaborations Communication Data Deposition Development Endocytosis Energy Metabolism Event Excision Exhibits Family member Fatty acid glycerol esters Functional disorder Gene Expression Genetic Glucose Health High Fat Diet Homeostasis Human Impairment In Vitro LDL-Receptor Related Protein 1 Laboratories Lead Ligands Link Lipids Low Density Lipoprotein Receptor Measures Mechanics Metabolic Metabolic Bone Diseases Metabolic Pathway Metabolism Modeling Mus Mutant Strains Mice Mutation Obesity Osteoblasts Osteopenia Osteoporosis PTH gene Peripheral Phase Physiological Prevalence Property Regulation Research Design Role Series Signal Pathway Signal Transduction Skeletal Development Skeleton Societies Stimulus Syndrome Testing Tissues Work bone bone mass chemical genetics energy balance fatty acid metabolism fatty acid oxidation gene repression genetic approach glucose metabolism glucose uptake in vivo innovation insight lipid metabolism lipoprotein receptor related protein 5 macromolecule malonyl-CoA decarboxylase metabolic phenotype mineralization mouse model mutant novel novel strategies osteoblast differentiation oxidation postnatal receptor response skeletal small molecule uptake

项目摘要

DESCRIPTION (provided by applicant): Since the identification of causative mutations in Lrp5 in osteoporosis-pseudoglioma and the high bone mass syndrome, the low-density lipoprotein receptor-related protein 5 (Lrp5) has been firmly linked with osteoblast function in humans and animal models. Work from several laboratories indicates that Wnt/Lrp/¿-catenin signaling is required for normal skeletal development and the full response of bone tissue to osteo-anabolic stimuli ranging from mechanical loading to parathyroid hormone. While attempting to distinguish the contributions of Lrp5 to bone development from those attributable to the highly related Lrp6, our laboratory identified a previously unanticipated function of Lrp5 in osteoblasts. In addition t the expected deficits in bone volume, mice lacking Lrp5 specifically in osteoblasts exhibited a dramatic increase in peripheral adiposity in association with reduced whole body energy expenditure. Moreover, ablation of Lrp5 in vitro reduced lipid oxidation during osteoblast differentiation and led to the down-regulation of genes involved in this metabolic pathway. These data suggest that Lrp5 regulates osteoblast metabolism and thereby allows bone to contribute to whole body energy balance. We hypothesize that such actions involve the biochemical properties of Lrp5 that are characteristic of low-density lipoprotein receptor family members. In this project, we will (1) define the requirement for Lrp5 in osteoblast fuel metabolism and (2) determine the impact of Wnt signaling on osteoblast metabolism and body composition. These studies take advantage of innovative genetic mouse models that enable osteoblast-restricted manipulation of fatty acid metabolism and Wnt signaling to uncover the mechanisms by which Lrp5 functions in normal metabolism.

描述（由申请人提供）：自从鉴定出骨质疏松症-假性神经胶质瘤和高骨量综合征中 Lrp5 的致病突变以来，低密度脂蛋白受体相关蛋白 5 (Lrp5) 已与人类和动物的成骨细胞功能紧密相关多个实验室的工作表明 Wnt/Lrp/¿ -连环蛋白信号是正常骨骼发育和骨组织对从机械负荷到甲状旁腺激素等骨合成代谢刺激的充分反应所必需的。在试图区分 Lrp5 对骨骼发育的贡献与高度相关的 Lrp6 的贡献时，我们发现发现了 Lrp5 在成骨细胞中的先前未预料到的功能，除了预期的骨体积缺陷之外，在成骨细胞中特别缺乏 Lrp5 的小鼠表现出实验室外周脂肪显着增加，并与骨体积减少相关。此外，体外消除 Lrp5 会减少成骨细胞分化过程中的脂质氧化，并导致参与该代谢途径的基因下调。这些数据表明，Lrp5 调节成骨细胞代谢，从而使骨骼对整个身体做出贡献。我们追求这种作用涉及 Lrp5 的生化特性，这是低密度脂蛋白受体家族成员的特征。在这个项目中，我们将 (1) 定义成骨细胞燃料中对 Lrp5 的要求。 (2) 确定 Wnt 信号传导对成骨细胞代谢和身体成分的影响这些研究利用创新的基因小鼠模型，使成骨细胞能够限制脂肪酸代谢和 Wnt 信号传导，以揭示 Lrp5 在正常情况下发挥作用的机制。代谢。