HIFs in osteocytes

骨细胞中的 HIF

基本信息

批准号：
10531534
负责人：
DAMIAN C GENETOS
金额：
$ 44.53万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10531534
关键词：
Age Aging Anabolism Attention Attenuated Bone Growth Cell Survival Cell physiology Cre driver Data Development Disease Down-Regulation Estrogens Fracture Gene Targeting Genes Genetic Genetic Epistasis Genetic Transcription Goals HIF1A gene Human Hypoxia Hypoxia Inducible Factor Incidence Individual LoxP-flanked allele Measures Mediating Medical Menopause Molecular Motivation Mus Mutation Osteoblasts Osteocytes Osteoporosis Ovariectomy Pathway interactions Phenotype Property Protein Isoforms Publishing Quality of life Reporting Resistance Rodent Role Signal Pathway Signal Transduction Skeletal Development Skeleton Specificity Testing Tumor Suppressor Proteins Ubiquitination Up-Regulation WNT Signaling Pathway Wild Type Mouse Work aging population beta catenin bone bone cell bone health bone loss bone mass cell type cost dentin matrix protein 1 improved mouse model new therapeutic target normoxia novel osteoporosis with pathological fracture osteoprogenitor cell pharmacologic prevent receptor response restoration skeletal socioeconomics ubiquitin-protein ligase

项目摘要

Project Summary There is a critical socioeconomic and medical need for anabolic therapies capable of replacing lost bone mass in diseases such as osteoporosis. Humans and mice with striking high bone mass (HBM) can aid in the identification of novel mechanisms to promote osteoanabolism. Notable examples include activating mutations in the Wnt co-receptor Lrp5 and individuals with sclerosteosis (decreased SOST expression). We have found that deletion of Vhl in osteocytes but not osteoblasts (Dmp1-cre;Vhlf/f) produces a robust skeletal phenotype, characterized by dramatic increases in both cortical and trabecular microarchitecture compared to age-matched wild-type mice. Vhl targets hypoxia inducible factor-alpha (HIF-a) subunits for ubiquitination and subsequent proteasomal degradation under normoxic conditions, and is considered a master regulator of HIF activity. In contrast to previous work deleting Hif1a in osteoblasts, we do not observe a reciprocal, low bone mass phenotype in osteocytes lacking Hif1a. Our data suggest that osteocytes may only require HIF-2a to transduce Vhl signaling, presenting new possibilities to identify and exploit yet-unknown pathways in osteocytes, that could be harnessed to improve bone health. It is not that surprising that osteoblasts and osteocytes might use different signaling machinery to transduce a particular signal, as a multitude of genes undergo upregulation or downregulation during the osteoblast-to-osteocyte transition. Increasing evidence shows that while HIF-1a and HIF-2a are both expressed in bone cells, their stability is differentially regulated, and they induce transcription of distinct gene targets. While much attention has focused on the role of HIF-1a in bone, very little is known about HIF-2a. Our long-term goal is to elucidate HIF-a isoform contribution to skeletal development, HIF-a isoform functional redundancy, integration with Wnt/b-catenin signaling, and if manipulation of Vhl/HIF-a expression prevents ovariectomy (OVX)-induced bone loss. Our overall hypothesis is that osteocytes require HIF-2a, rather than HIF-1a, to mediate effects on the skeleton. Within, we will evaluate the fundamental requirement of OCY HIF-2a in longitudinal bone growth, as well as HIF-a isoform specificity to recapitulate and maintain the Vhl cKO HBM phenotype (Aim 1), the epistatic relationship of b-catenin in the HBM phenotype of Vhl cKO mice (Aim 2), and the utility of targeting HIF-a for improving bone properties in an OVX mouse model (Aim 3). These studies will define the role of HIF-a-dependent functions of Vhl in osteocytes that drive acquisition of HBM. Understanding these signaling pathways may allow identification of novel therapeutic targets leading to bone accrual and reversing the osteoporosis that accompanies aging and menopause. Doing so will alleviate the costs and associated quality of life issues that result in the inevitable fractures that are so common, without the associated complications that accompany current therapy.

项目摘要对于能够取代骨骼损失的合成疗法的社会经济和医疗需求至关重要疾病中的肿块，例如骨质疏松症。人类和具有惊人高骨质量（HBM）的小鼠可以帮助鉴定新的机制以促进骨代谢。著名的例子包括激活突变在Wnt共受体LRP5中，患有硬化症的个体（SOST表达降低）。我们发现，在整骨细胞中删除VHL，而不是成骨细胞（dmp1-cre; vhlf/f）产生强大的骨骼表型，以皮质和小梁微体系结构的急剧增加为特征与年龄匹配的野生型小鼠相比。 VHL靶向缺氧诱导因子-Alpha（HIF-A）亚基的目标泛素化和随后的蛋白酶体降解在常氧化条件下，被认为是一种 HIF活动的主调节器。与以前在成骨细胞中删除HIF1A的工作相反，我们不观察到缺乏HIF1A的骨细胞中的相互骨质量表型。我们的数据表明骨细胞只能需要HIF-2A传递VHL信号，提出了新的可能性来识别和利用迄今未知骨细胞中的途径可以利用以改善骨骼健康。成骨细胞和成骨细胞可能会使用不同的信号机械来毫不奇怪传递特定信号，因为多种基因在此期间经历上调或下调成骨细胞到骨细胞的过渡。越来越多的证据表明，尽管HIF-1A和HIF-2A都是在骨细胞中表达，其稳定性受到差异调节，它们诱导了不同基因的转录目标。尽管很多关注的关注点关注HIF-1A在骨骼中的作用，但对HIF-2A的了解很少。我们的长期目标是阐明HIF-A同工型对骨骼发育的贡献，HIF-A同工型功能冗余，与Wnt/B-catenin信号的集成，以及是否操纵VHL/HIF-A表达防止卵巢切除术（OVX）诱导的骨质流失。我们的总体假设是骨细胞需要HIF-2A，而不是HIF-1A，以介导对骨骼的影响。内部，我们将评估 OCY HIF-2A在纵向骨生长中以及HIF-A同工型特异性，以概括和维持 VHL CKO HBM表型（AIM 1），B-catenin在VHL CKO的HBM表型中的上皮关系小鼠（AIM 2），以及针对HIF-A在OVX小鼠模型中改善骨特性的实用性（AIM 3）。这些研究将定义VHL的HIF-A依赖性功能在驱动获得的骨细胞中的作用 HBM。了解这些信号通路可能允许识别新的治疗靶标的骨骼应计并逆转衰老和更年期伴随的骨质疏松症。这样做会减轻成本和相关的生活质量问题导致不可避免的裂缝如此普遍，没有当前疗法伴随的并发症。