Regulation of Osteoblast Metabolism by Lrp5

Lrp5 对成骨细胞代谢的调节

• 批准号: 8845550
• 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
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-24 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8845550
• 关键词: Ablation; Address; Alleles; Animal Model; Biochemical; Biochemistry; Biology; Body Composition; Bone Development; Bone Tissue; Characteristics; Collaborations; Communication; Data; Deposition; Development; Diet; Endocytosis; Energy Metabolism; Event; Excision; Exhibits; Family member; Fatty acid glycerol esters; Functional disorder; Gene Expression; Genetic; Glucose; Health; Homeostasis; Hormones; 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; Parathyroid gland; Peripheral; Phase; Phenotype; 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; mineralization; mouse model; mutant; novel; novel strategies; osteoblast differentiation; oxidation; postnatal; receptor; response; skeletal; small molecule; uptake

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（由应用提供）：由于骨质疏松症中的LRP5中结构突变的鉴定和高骨质量综合征，因此首先将低密度脂蛋白受体相关蛋白相关蛋白相关的蛋白质（LRP5）与人类和动物模型中的成骨功能联系起来。来自几个实验室的工作表明，正常骨骼发育需要Wnt/LRP/� -Catenin信号传导，以及骨组织对骨 - 抗代谢刺激的全部响应，从机械载荷到甲状旁腺甲烯。在试图区分LRP5对骨骼发育的贡献与高度相关的LRP6的贡献，我们的实验室确定了成骨细胞中LRP5的先前意外功能。此外，骨体积的预期缺乏，缺乏LRP5的小鼠特别是在成骨细胞中，与全身能量消耗减少相关的外周肥胖症的急剧增加。此外，在成骨细胞分化过程中，LRP5在体外消融脂质氧化，并导致该代谢途径中涉及的基因的下调。这些数据表明LRP5调节成骨细胞代谢，从而使骨骼有助于全身能量平衡。我们假设这种作用涉及以低密度脂蛋白受体家族成员为特征的LRP5的生化特性。在这个项目中，我们将（1）定义成骨细胞燃料代谢中LRP5的需求，（2）确定Wnt信号对成骨细胞代谢和身体组成的影响。这些研究利用了创新的遗传小鼠模型，这些模型能够对脂肪酸代谢和WNT信号传导进行成骨细胞限制的操纵，以发现LRP5在正常代谢中起作用的机制。