Regulation of Osteoblast Metabolism by Lrp5

描述（由申请人提供）：自从在骨质疏松-假性胶质瘤和高骨量综合征中发现Lrp5的致病突变以来，低密度脂蛋白受体相关蛋白5 （Lrp5）在人和动物模型中与成骨细胞功能紧密相关。几个实验室的工作表明，Wnt/Lrp/¿-catenin信号是正常骨骼发育和骨组织对骨合成代谢刺激（从机械负荷到甲状旁腺激素）的全面反应所必需的。在试图区分Lrp5对骨发育的贡献与高度相关的Lrp6的贡献时，我们的实验室发现了Lrp5在成骨细胞中以前未预料到的功能。除了预期的骨体积缺陷外，成骨细胞中缺乏Lrp5的小鼠外周脂肪显著增加，并伴有全身能量消耗减少。此外，体外消融Lrp5可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，从而使骨骼有助于全身能量平衡。我们假设这种作用涉及Lrp5的生化特性，这些特性是低密度脂蛋白受体家族成员的特征。在本项目中，我们将(1)明确成骨细胞燃料代谢对Lrp5的需求；(2)确定Wnt信号对成骨细胞代谢和体成分的影响。这些研究利用创新的遗传小鼠模型，使成骨细胞限制脂肪酸代谢和Wnt信号的操纵，揭示了Lrp5在正常代谢中的作用机制。

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.