Regulation of Osteoblast Metabolism by Lrp5

Lrp5 对成骨细胞代谢的调节

• 批准号: 10721607
• 负责人: Ryan C Riddle
• 金额: $ 30.91万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-10 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10721607
• 关键词: Regulation; Osteoblast; Metabolism; Lrp5

Abstract 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. In the previous funding period, we demonstrated that Wnt/b-catenin signaling through Lrp5 regulates long-chain fatty acid utilization by the osteoblast. Thus, transgenic mice lacking Lrp5 specifically in the osteoblast exhibited an increase in adipose tissue mass and developed a dyslipidemia in addition to the expected low bone mass phenotype. Moreover, genetic ablation of Cpt2, an obligate enzyme in long chain fatty acid catabolism, in the osteoblast impairs bone acquisition and led to an increase in serum lipids. Together, these data suggest that bone is a site of significant fatty acid utilization and that the regulation of osteoblast metabolism by Lrp5 contributes to both bone accrual and whole body energy balance. In this renewal application we will use genetic mouse models to (1) determine the mechanism by which fatty acids are acquired by the osteoblast and (2) assess the metabolic substrate requirements that are necessary for Wnt-stimulated bone formation. We hypothesize that fatty acid uptake will require the actions of Slc27a1 and/or CD36 and that inhibition of fatty acid utilization will be sufficient to inhibit the Wnt-induced increase in bone formation associated with Sost deficiency or expression of a Lrp5 high bone mass allele. These studies will further our understanding of the metabolic requirements of bone formation, the contribution of bone to metabolism, and the mechanisms by which Wnt/b-catenin signaling govern skeletal homeostasis.

摘要

项目成果

Parathyroid Hormone Reprograms Osteoblast Metabolism.

• DOI: 10.1002/jbmr.2727
• 发表时间: 2015-11
• 期刊: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
• 作者: Riddle RC