Regulation of Osteoblast Metabolism by Lrp5

描述（由申请人提供）：自从在骨肉瘤-假胶质瘤和高骨量综合征中鉴定出Lrp 5的致病突变以来，低密度脂蛋白受体相关蛋白5（Lrp 5）已在人类和动物模型中与成骨细胞功能牢固相关。来自几个实验室的工作表明，Wnt/Lrp/<$-连环蛋白信号传导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Lrp 5对骨发育的贡献与高度相关的Lrp 6的贡献时，我们的实验室确定了Lrp 5在成骨细胞中的一种以前未预料到的功能。除了预期的骨体积缺陷之外，成骨细胞中特异性缺乏Lrp 5的小鼠表现出与全身能量消耗减少相关的外周肥胖症的显著增加。此外，体外Lrp 5的消融减少了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，Lrp 5调节成骨细胞代谢，从而使骨骼有助于全身能量平衡。我们推测，这些行动涉及Lrp 5的生化特性，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）确定成骨细胞燃料代谢对Lrp 5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，使成骨细胞限制性操纵脂肪酸代谢和Wnt信号，以揭示Lrp 5在正常代谢中发挥作用的机制。

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.