The Role of Irisin in Initiating Resorption During the Skeletal Response to Exercise

鸢尾素在骨骼运动反应过程中启动吸收的作用

基本信息

批准号：
10572067
负责人：
Eben Grant Estell
金额：
$ 12.74万
依托单位：
MAINEHEALTH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10572067
关键词：
Address Adipose tissue Affect Alleles Anabolism Back Binding Proteins Bone Density Bone Diseases Bone Resorption Bone remodeling Brain Calcium Calcium Signaling Catabolism Cell Line Cell Nucleus Cell membrane Cell model Cells Chemicals Coculture Techniques Coupling Cues Degenerative Disorder Dose Equilibrium Estrogens Event Exercise Fibronectins Future Genetic Genetic Transcription Homeostasis Hormones Image In Vitro Infusion procedures Integrins Investigation Knockout Mice Liquid substance LoxP-flanked allele Maintenance Mediating Mitochondria Modeling Mus Muscle Osteoblasts Osteoclasts Osteocytes Osteogenesis Ovariectomy Pathway interactions Peptide Signal Sequences Physiological Protein Secretion Proteins Proteomics Regulation Research Respiration Role Serum Signal Pathway Signal Transduction Skeletal Development Skeletal Muscle TRANCE protein Techniques Testing Therapeutic Thick Tissue Model Tissues Wild Type Mouse Work aging population bone bone health bone loss chemical release conditional knockout cortical bone deprivation experimental study functional outcomes genetic approach in vivo in vivo Model insight mechanical signal mechanical stimulus novel osteoclastogenesis pleiotropism prevent programs receptor release factor response skeletal therapeutic development transcriptome sequencing

Address Adipose tissue Affect Alleles Anabolism Back Binding Proteins Bone Density Bone Diseases Bone Resorption Bone remodeling Brain Calcium Calcium Signaling Catabolism Cell Line Cell Nucleus Cell membrane Cell model Cells Chemicals Coculture Techniques Coupling Cues Degenerative Disorder Dose Equilibrium Estrogens Event Exercise Fibronectins Future Genetic Genetic Transcription Homeostasis Hormones Image In Vitro Infusion procedures Integrins Investigation Knockout Mice Liquid substance LoxP-flanked allele Maintenance Mediating Mitochondria Modeling Mus Muscle Osteoblasts Osteoclasts Osteocytes Osteogenesis Ovariectomy Pathway interactions Peptide Signal Sequences Physiological Protein Secretion Proteins Proteomics Regulation Research Respiration Role Serum Signal Pathway Signal Transduction Skeletal Development Skeletal Muscle TRANCE protein Techniques Testing Therapeutic Thick Tissue Model Tissues Wild Type Mouse Work aging population bone bone health bone loss chemical release conditional knockout cortical bone deprivation experimental study functional outcomes genetic approach in vivo in vivo Model insight mechanical signal mechanical stimulus novel osteoclastogenesis pleiotropism prevent programs receptor release factor response skeletal therapeutic development transcriptome sequencing

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项目摘要

Irisin is a novel signaling peptide proteolyzed from the cell membrane-bound protein Fndc5 (fibronectin type III domain-containing protein 5), first described by our collaborators to release from muscle during exercise and induce a thermogenic program in beige adipose tissue. A growing body of work has highlighted another key role for irisin in mediating the effect of exercise on bone. Early work described an anabolic action, with intermittent low doses of irisin stimulating cortical bone formation and preventing unloading-induced bone loss in vivo, and serum-derived irisin from exercised mice enhancing osteoblastogenesis in vitro. Our group has employed a genetic approach to further elucidate the role of irisin in skeletal remodeling, demonstrating that forced expression of Fndc5 in muscle markedly reduced bone formation and osteoblast numbers while increasing sclerostin (SOST) expression and osteoclast numbers. Global genetic deletion of Fndc5 conferred complete protection against ovariectomy-induced bone loss, marked by maintenance of osteocyte lacunae and blocked bone resorption with no increases in Receptor Activator of Nuclear Factor Kappa-β Ligand (RANKL) expression despite prolonged estrogen deprivation. Similarly, short term irisin infusions in wild type mice resulted in higher serum levels of sclerostin and RANKL. These results highlight the breadth of irisin’s signaling effects in bone, and the need to further understand its overall impact on resorption and remodelling. We now have additional evidence that irisin signals directly to the osteoclast via integrin αVβ5, stimulating differentiation and resorption. The present work endeavors to delineate the full signaling pathway in the osteoclast, while employing novel in vivo models to test this regulation of resorption in the context of skeletal response to exercise. We have developed a novel conditional mouse allele of Fndc5 and generated a skeletal muscle- specific targeted null, which we will use to test the effect of muscle-derived irisin on bone response to exercise. In parallel, we will utilize in vitro techniques to confirm the putative receptors for irisin and characterize intracellular signal transduction in the osteoclast. To comprehensively assess irisin’s impact on bone resorption, we will also investigate indirect effects of irisin on the osteoclast, through regulation by the osteocyte. Finally, as osteocyte response to mechanical cues is a key aspect of this cell’s function during exercise, we will investigate the potential interplay between irisin signaling and mechanosensitivity. We predict pleiotropic effects of irisin – it may be a coupling factor by directly stimulating both the osteoblast and osteoclast, and also serve a unique role as a counter regulatory hormone to maintain calcium homeostasis by increasing resorption. By focusing on the osteoclast, this work seeks to elucidate irisin’s role in initiating bone resorption and better understand its influence on remodeling as a whole. Such insights both provide a greater understanding of skeletal response to exercise but inform efforts to address bone degenerative diseases by taking advantage of native signaling pathways.

虹膜蛋白是一种从细胞膜结合的蛋白FNDC5（纤连蛋白III型）的新型信号肽蛋白水解含域的蛋白质5），首先由我们的合作者描述，是在运动期间从肌肉中释放出来的在米色脂肪组织中诱导热程序。越来越多的工作突出了另一个钥匙虹膜蛋白在介导运动对骨骼的影响中的作用。早期工作描述了合成代谢作用，间歇性低剂量的虹膜蛋白刺激皮质骨形成并防止卸载引起的骨质流失体内和来自运动小鼠的血清衍生的虹膜蛋白在体外增强成骨细胞生成。我们的小组有采用一种遗传方法来进一步阐明虹膜蛋白在骨骼重塑中的作用，表明 FNDC5在肌肉中的强迫表达显着降低了骨形成和成骨细胞数量增加硬化素（SOST）表达和破骨细胞数。 FNDC5的全球遗传缺失完全保护卵巢切除术引起的骨质损失，以维持骨细胞腔和骨骼分辨率阻塞，核因子Kappa-β配体（RANKL）的受体激活剂无增加表达延长雌激素剥夺。同样，野生型小鼠的短期虹膜蛋白输注导致较高的血清硬化蛋白和RANKL水平。这些结果突出了虹膜信号传导的广度对骨骼的影响，以及进一步了解其对分辨率和重塑的总体影响的需求。我们现在还有其他证据表明虹膜蛋白通过整合素αVβ直接向破骨细胞信号，刺激分化和解决方案。目前的工作努力描绘破骨细胞中的完整信号通路，而采用新颖的体内模型在骨骼反应的背景下测试该分辨率的调节锻炼。我们已经开发了一个新型的有条件小鼠的FNDC5等位基因，并产生了骨骼肌 - 特定的靶向零，我们将用来测试肌肉衍生的虹膜蛋白对运动骨反应的影响。同时，我们将利用体外技术来确认虹膜蛋白的假定受体并表征破骨细胞中的细胞内信号转导。全面评估虹膜蛋白对骨骼的影响解决方案，我们还将通过通过调节来调查虹膜蛋白对破骨细胞的间接影响骨细胞。最后，由于骨细胞对机械提示的响应是该单元格期间该单元功能的关键方面练习，我们将研究虹膜蛋白信号传导和机械敏感性之间的潜在相互作用。我们预测虹膜蛋白的多效作用 - 它可能是直接刺激成骨细胞和成骨细胞和破骨细胞，还扮演着一个独特的角色，作为计数器调节骑马，可维持钙稳态增加分辨率。通过专注于破骨细胞，这项工作旨在阐明艾里森在发起骨骼中的作用解决方案并更好地了解其对整个重塑的影响。这些见解都提供了更大的理解骨骼对运动的反应，但可以为解决骨骼退化性疾病的努力提供信息利用天然信号通路。