Regulation of Osteoblast Metabolism by Lrp5

摘要 LRP5基因突变在骨质疏松-假性胶质瘤和高骨量中的发现 低密度脂蛋白受体相关蛋白5(LRP5)与成骨细胞密切相关 在人类和动物模型中发挥作用。在上一个资助期，我们证明了Wnt/b-catenin 通过LRP5信号调节成骨细胞对长链脂肪酸的利用。因此，转基因小鼠 成骨细胞中缺乏LRP5会导致脂肪组织质量增加，并发展为 除了预期的低骨量表型外，还有血脂异常。此外，Cpt2、And和Cpt2的基因消融 成骨细胞中长链脂肪酸分解代谢中的专性酶损害骨获取并导致 血脂升高。综上所述，这些数据表明骨骼是一个重要的脂肪酸利用部位和 LRP5对成骨细胞代谢的调节有助于骨积累和全身能量的增加 平衡。在此更新应用程序中，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)评估代谢底物的需求 对于WNT刺激的骨形成来说是必需的。我们假设脂肪酸的摄取将需要 SLC27a1和/或CD36以及对脂肪酸利用抑制将足以抑制WNT诱导的 与SOST缺乏或表达LRP5高骨量等位基因相关的骨形成增加。 这些研究将进一步加深我们对新陈代谢要求的骨形成的贡献 以及Wnt/b-catenin信号调控骨骼动态平衡的机制。

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.