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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Molecular and Cellular Endocrinology Study Section (MCE)
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Malozowski, Saul N
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Johns Hopkins University
Schools of Medicine
United States
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Frey, Julie L; Kim, Soohyun P; Li, Zhu et al. (2018) ?-Catenin Directs Long-Chain Fatty Acid Catabolism in the Osteoblasts of Male Mice. Endocrinology 159:272-284
Moorer, Megan C; Riddle, Ryan C (2018) Regulation of Osteoblast Metabolism by Wnt Signaling. Endocrinol Metab (Seoul) 33:318-330
Kushwaha, Priyanka; Wolfgang, Michael J; Riddle, Ryan C (2018) Fatty acid metabolism by the osteoblast. Bone 115:8-14
Riddle, Ryan C; Clemens, Thomas L (2017) Bone Cell Bioenergetics and Skeletal Energy Homeostasis. Physiol Rev 97:667-698
Kim, Soohyun P; Li, Zhu; Zoch, Meredith L et al. (2017) Fatty acid oxidation by the osteoblast is required for normal bone acquisition in a sex- and diet-dependent manner. JCI Insight 2:
Lee, Jieun; Choi, Joseph; Selen Alpergin, Ebru S et al. (2017) Loss of Hepatic Mitochondrial Long-Chain Fatty Acid Oxidation Confers Resistance to Diet-Induced Obesity and Glucose Intolerance. Cell Rep 20:655-667
Kim, Soohyun P; Frey, Julie L; Li, Zhu et al. (2017) Sclerostin influences body composition by regulating catabolic and anabolic metabolism in adipocytes. Proc Natl Acad Sci U S A 114:E11238-E11247
Kim, Soohyun P; Frey, Julie L; Li, Zhu et al. (2017) Lack of Lrp5 Signaling in Osteoblasts Sensitizes Male Mice to Diet-Induced Disturbances in Glucose Metabolism. Endocrinology 158:3805-3816
Zoch, Meredith L; Abou, Diane S; Clemens, Thomas L et al. (2016) In vivo radiometric analysis of glucose uptake and distribution in mouse bone. Bone Res 4:16004
Zoch, Meredith L; Clemens, Thomas L; Riddle, Ryan C (2016) New insights into the biology of osteocalcin. Bone 82:42-9

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