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

淫羊藿素是从细胞膜结合蛋白FNDC5(纤维连接蛋白III型)中分离出来的一种新的信号肽 含有结构域的蛋白5)，首先由我们的合作者描述，在运动和运动过程中从肌肉中释放 在米色脂肪组织中诱导一个产热程序。越来越多的著作突显了另一个关键 淫羊藿素在调节运动对骨骼影响中的作用。早期的工作描述了一种合成代谢作用， 间歇性小剂量淫羊藿素促进皮质骨形成和预防卸载性骨丢失 在体内，以及运动小鼠的血清来源的淫羊藿素在体外促进成骨细胞的形成。我们的团队已经 用遗传学的方法进一步阐明了虹膜蛋白在骨骼重塑中的作用，证明了 FNDC5在肌肉中的强制表达显著减少骨形成和成骨细胞数量，而 增加硬化素(Sost)的表达和破骨细胞的数量。FNDC5基因的全球缺失被授予 完全防止卵巢切除引起的骨丢失，其特点是维持骨细胞陷窝和 核因子Kappa-β受体激活剂配基NO增加阻断骨吸收 尽管长期缺乏雌激素，但仍有表达。同样，在野生型小鼠中短期注射淫羊藿素 导致血清硬化素和RANKL水平升高。这些结果突出了淫羊藿素信号的广度 对骨骼的影响，以及进一步了解其对吸收和重塑的整体影响的必要性。我们现在 有更多证据表明，虹膜蛋白通过整合素αVβ5直接向破骨细胞发出信号，刺激分化 和再吸收。目前的工作致力于描绘完整的信号通路在破骨细胞，而 使用新的体内模型来测试这种吸收调节的骨骼反应 锻炼身体。我们已经开发出一种新的FNDC5条件性小鼠等位基因，并产生了一种骨骼肌- 特异靶向空，我们将用它来测试肌肉衍生的虹膜对骨骼运动反应的影响。 同时，我们将利用体外技术来确认虹膜蛋白可能的受体并确定其特征。 破骨细胞的细胞内信号转导。全面评价淫羊藿素对骨骼的影响 除了吸收，我们还将研究淫羊藿素对破骨细胞的间接影响，通过调节 骨细胞。最后，由于骨细胞对机械提示的反应是该细胞在 通过运动，我们将研究虹膜蛋白信号和机械敏感性之间的潜在相互作用。我们预测 淫羊藿素的多效性--它可能是一种偶联因子，通过直接刺激成骨细胞和 破骨细胞，也发挥着独特的作用，作为一种反调节激素，通过 不断增加的再吸收。通过重点研究破骨细胞，这项工作试图阐明淫羊藿素在启动骨骼中的作用 并更好地了解其对整体重塑的影响。这样的洞察力既提供了更大的 了解骨骼对运动的反应，但有助于通过以下方式解决骨骼退行性疾病 利用本地信号通路。

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.