Extracellular regulation of bone mass by transforming growth factor-ß-related ligands and their binding proteins

通过转化生长因子相关配体及其结合蛋白对骨量进行细胞外调节

基本信息

批准号：
10537833
负责人：
EMILY L GERMAIN-LEE
金额：
$ 63.89万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-21 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10537833
关键词：
ACVR2 gene ACVR2B gene Activin A type II receptor Activins Acute Affect Binding Proteins Bone Density Bone Diseases Bone structure Chronic Complex Development Differentiation and Growth Family member Follistatin GDF8 gene Genetic Genetic study Goals Growth Health Homeostasis Individual Ligands LoxP-flanked allele Molecular Mus Muscle Names Osteoblasts Pathway interactions Patients Pharmacology Pharmacology Study Physiological Play Regulation Regulatory Pathway Role Signal Pathway Signal Transduction Signaling Molecule Skeletal Muscle Subgroup System TGF-beta type I receptor Tissues Transforming Growth Factors Work activin A bone bone loss bone mass clinical application extracellular genetic approach interest morphogens muscle form novel therapeutic intervention preservation prevent receptor skeletal muscle growth stem tool virtual

项目摘要

The focus of this project will be to investigate the role of the myostatin/GDF-11/activin branch of the transforming growth factor-ß (TGF-ß) superfamily of secreted signaling molecules in regulating bone mass and density. The important role that this signaling pathway plays in regulating bone homeostasis has been documented by both pharmacologic and genetic studies targeting receptors for this group of ligands. Work from several groups, including ours, has shown that systemic administration of soluble forms of either of the activin type 2 receptors, ACVR2 and ACVR2B, is capable of inducing significant increases in bone density. By genetically targeting these receptors in osteoblasts, we showed that at least part of this effect is due to inhibition of direct signaling to bone. Strikingly, however, we very recently showed that targeting the type 1 receptors, ALK4 and ALK5, in osteoblasts led to much more substantial effects, resulting in increases in bone mass and density by approximately 10-fold. These findings revealed the extraordinary capacity for bone accrual that is normally kept in check by this regulatory system and suggest that the potential for increasing bone mass and density by targeting this signaling pathway is substantially greater than previously appreciated. As a starting point for developing the most effective strategies to harness the potential of targeting this pathway for bone applications, we will elucidate the extracellular components that play key roles in this regulatory network in bone. In Specific Aim 1, we will examine the roles of known inhibitory binding proteins for this group of ligands in regulating bone structure. In our recent study, we carried out an extensive analysis of the role of one binding protein, namely follistatin (FST), using genetically-targeted mouse lines in which expression levels of FST were either up- or down-regulated. Here, we will examine the roles of the three other known binding proteins, FSTL-3, GASP-1, and GASP-2, utilizing targeted mouse lines that we have generated carrying both deletion and floxed alleles for each of these components. In Specific Aim 2, we will examine the roles of specific ligands in this subgroup of the TGF-ß superfamily in regulating bone structure. In our recent study, we showed that targeting two ligands simultaneously, namely myostatin and activin A, led to substantial increases in bone mass and density but that these increases were significantly less pronounced than the approximately 10-fold effects that we observed upon targeting their type 1 receptors. Here, we will use genetic approaches to examine the roles of a wider spectrum of ligands in this subgroup of the TGF-ß superfamily in regulating bone structure. The overall goal of this project will be to elucidate the specific extracellular signaling components that play key roles in regulating bone homeostasis with the long-term goal of developing the most effective strategies to target this signaling pathway to treat bone loss.

该项目的重点是研究肌生长抑制素/GDF-11/激活素分支的作用分泌信号分子的转化生长因子-β（TGF-β）超家族在调节骨量和该信号通路在调节骨稳态中发挥着重要作用。针对这组配体的受体的药理学和遗传学研究记录了这一点。包括我们在内的几个小组的研究表明，系统性施用任何一种的可溶形式激活素 2 型受体 ACVR2 和 ACVR2B 能够诱导骨密度显着增加。通过基因靶向成骨细胞中的这些受体，我们发现这种效应至少部分归因于然而，令人惊讶的是，我们最近发现针对 1 型的直接信号传导的抑制。成骨细胞中的 ALK4 和 ALK5 受体会产生更显着的影响，导致骨密度增加这些发现揭示了骨的非凡能力。应计费用通常受到该监管体系的控制，并表明增加的潜力通过靶向该信号通路，骨量和密度大大高于之前的认识。作为制定最有效策略以利用针对该途径的潜力的起点对于骨骼应用，我们将阐明在这种调节中发挥关键作用的细胞外成分在具体目标 1 中，我们将研究已知的抑制性结合蛋白在该组中的作用。在我们最近的研究中，我们对配体在调节骨结构中的作用进行了广泛的分析。一种结合蛋白，即卵泡抑素（FST），使用基因靶向小鼠品系，其中表达水平 FST 的上调或下调在这里，我们将检查其他三种已知结合的作用。蛋白质 FSTL-3、GASP-1 和 GASP-2，利用我们生成的携带这两种蛋白质的靶向小鼠品系在具体目标 2 中，我们将研究每个组件的缺失和 floxed 等位基因的作用。在我们最近的研究中，我们发现了 TGF-β 超家族这一亚组中的特定配体在调节骨结构方面的作用。表明同时靶向两个配体，即肌肉生长抑制素和激活素 A，导致显着增加骨量和密度的增加，但这些增加明显不如大约我们在针对 1 型受体时观察到的 10 倍效应在这里，我们将使用遗传方法来实现。检查 TGF-β 超家族亚组中更广泛的配体在调节骨中的作用该项目的总体目标是阐明特定的细胞外信号传导成分。在调节骨稳态中发挥关键作用，长期目标是开发最有效的针对该信号通路来治疗骨质流失的策略。