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

• 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
• 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

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.

该项目的重点将是调查肌肉生长抑素/GDF-11/激活素分支的作用 转化生长因子超家族分泌信号分子在骨量调节中的作用 密度。这一信号通路在调节骨骼内环境平衡中发挥的重要作用 针对这组配体的受体的药理学和遗传学研究都证明了这一点。工作 来自包括我们在内的几个小组的研究表明，系统性地给药 激活素2型受体ACVR2和ACVR2B能够诱导骨密度显著增加。通过 通过基因定位成骨细胞中的这些受体，我们表明，这种影响至少有一部分是由于 抑制对骨骼的直接信号。然而，引人注目的是，我们最近表明，针对类型1 成骨细胞中的受体ALK4和ALK5导致更多的实质性作用，从而导致骨骼的增加 质量和密度增加了大约10倍。这些发现揭示了骨骼的非凡能力 通常由这一监管系统控制的应计项目，表明增加的可能性 靶向这一信号通路的骨量和密度比以前估计的要大得多。 作为开发最有效的战略以利用针对这一途径的潜力的起点 对于骨骼应用，我们将阐明在这一调节中起关键作用的细胞外成分。 骨子里的人脉。在特定的目标1中，我们将研究已知的抑制结合蛋白对这一组的作用 配体在调节骨骼结构中的作用。在我们最近的研究中，我们广泛地分析了 一种结合蛋白，即卵泡抑素(FST)，使用基因靶向的小鼠品系，在其中表达水平 FST的表达或上调或下调。在这里，我们将研究其他三个已知绑定的作用 蛋白质，FSTL-3，GASP-1和GASP-2，利用我们产生的携带这两种蛋白质的靶向鼠系 这些成分中的每一个都有缺失和突变的等位基因。在具体目标2中，我们将研究 这是转化生长因子超家族中调节骨结构的特定配体。在我们最近的研究中，我们 结果表明，同时靶向两种配体，即肌肉生长抑素和激活素A，导致显著增加 在骨量和密度方面，但这些增加明显没有大约 我们在靶向其1型受体时观察到的效果是10倍。在这里，我们将使用遗传方法来 研究转化生长因子超家族这一亚群中更广泛的配体在调节骨骼中的作用 结构。这个项目的总体目标将是阐明特定的细胞外信号成分 在调节骨骼动态平衡方面发挥关键作用，其长期目标是开发最有效的 以此信号通路为靶点治疗骨丢失的策略。