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.
This project will investigate a novel function for Lrp5 in skeletal homeostasis, wherein Lrp5 regulates osteoblast metabolism and allows bone to contribute to whole body energy balance. Characterizing the functions of Lrp5 may ultimately lead to the development of novel approaches for the treatment of both osteopenia and metabolic dysfunction.
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