Regulation of Osteoblast Metabolism by Lrp5

Lrp5 对成骨细胞代谢的调节

• 批准号: 10372036
• 负责人: Ryan C Riddle
• 金额: $ 8.18万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-24 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372036
• 关键词: Ablation; Adipose tissue; Affect; Alleles; Animal Model; Architecture; Biochemistry; Biology; Body Composition; Bone Diseases; CD36 Antigens; CD36 gene; Carbon; Carnitine Palmitoyltransferase I; Catabolism; Citric Acid Cycle; Collaborations; Crossbreeding; Data; Deposition; Development; Diabetes Mellitus; Dyslipidemias; Endocrine Glands; Enzymes; Exhibits; Fatty Acids; Funding; Genetic; Glucose; Glutamine; Glycolysis; Homeostasis; Impairment; In Vitro; LDL-Receptor Related Protein 1; Label; Lead; Ligands; Link; Lipids; Lipoprotein (a); Mediating; Metabolic; Metabolic Pathway; Metabolic dysfunction; Metabolism; Mitochondria; Molecular; Mus; Mutant Strains Mice; Obesity Epidemic; Organ; Osteoblasts; Osteogenesis; Osteopenia; Osteoporosis; Phase; Phenotype; Radiolabeled; Receptor Activation; Regulation; Research Design; Role; Series; Serum; Signal Transduction; Site; Skeletal Development; Suggestion; Syndrome; Tracer; Transgenic Mice; WNT Signaling Pathway; Work; beta catenin; bone; bone mass; causal variant; comorbidity; energy balance; experimental study; extracellular; fatty acid analog; fatty acid oxidation; human model; in vivo; insight; interest; lipid metabolism; lipoprotein receptor related protein 5; liquid chromatography mass spectroscopy; long chain fatty acid; microCT; mineralization; mouse model; mutant; novel strategies; osteoblast differentiation; oxidation; pyruvate carrier; response; skeletal; transcription factor; uptake

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 自从在神经胶质瘤-假胶质瘤和高骨量中鉴定出Lrp 5的致病突变以来， 低密度脂蛋白受体相关蛋白5（Lrp 5）与成骨细胞紧密相关， 在人类和动物模型中发挥作用。在前一个资助期，我们证明了Wnt/b-连环蛋白 通过Lrp 5的信号传导调节成骨细胞对长链脂肪酸的利用。因此，转基因小鼠 在成骨细胞中缺乏Lrp 5特异性表现出脂肪组织质量的增加， 血脂异常以及预期的低骨量表型。此外，Cpt 2的基因切除， 成骨细胞中的长链脂肪酸催化剂中的专性酶损害骨获取，并导致 血脂升高。总之，这些数据表明，骨骼是脂肪酸利用的重要场所， Lrp 5对成骨细胞代谢的调节有助于骨积累和全身能量 平衡在本更新申请中，我们将使用遗传小鼠模型来（1）通过以下方式确定机制： 哪些脂肪酸是由成骨细胞获得的，以及（2）评估 Wnt刺激的骨形成所必需的。我们假设脂肪酸的摄取需要以下的作用： Slc 27 a1和/或CD 36，并且脂肪酸利用的抑制将足以抑制Wnt诱导的细胞凋亡。 与Sost缺乏或Lrp 5高骨量等位基因表达相关的骨形成增加。 这些研究将进一步加深我们对骨形成的代谢要求的理解， 以及Wnt/β-连环蛋白信号调控骨骼稳态的机制。