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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Deletion of penostin reduces muscular dystrophy and fibrosis in mice by modulating the transforming growth factor-β pathway
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Deletion of penostin reduces muscular dystrophy and fibrosis in mice by modulating the transforming growth factor-β pathway

机译：Penostin的缺失通过调节转化生长因子-β途径减轻小鼠的肌肉营养不良和纤维化

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The muscular dystrophies are broadly classified as muscle wasting diseases with myofiber dropout due to cellular necrosis, inflammation, alterations in extracellular matrix composition, and fatty cell replacement. These events transpire and progress despite ongoing myofiber regeneration from endogenous satellite cells. The degeneration/regeneration response to muscle injury/disease is modulated by the proinflammatory cytokine transforming growth factor-β (TGF-β), which can also profoundly influence extracellular matrix composition through increased secretion of pro-fibrotic proteins, such as the matricellular protein periostin. Here we show that up-regulation and secretion of periostin is pathological and enhances disease in the δ-sarcoglycan null (Sgccd~(-/-)) mouse model of muscular dystrophy (MD). Indeed, MD mice lacking the Postn gene showed dramatic improvement in skeletal muscle structure and function. Mechanistically, Postn gene deletion altered TGF-β signaling so that it now enhanced tissue regeneration with reduced levels of fibrosis. Systemic antagonism of TGF-β with a neutralizing monoclonal antibody mitigated the beneficial effects of Postn deletion in vivo. These data suggest that periostin functions as a disease determinant in MD by promoting/allowing the pathological effects of TGF-β, suggesting that inhibition of periostin could represent a unique treatment approach.
机译：肌肉营养不良大致归类为肌肉萎缩性疾病，由于细胞坏死，炎症，细胞外基质组成改变和脂肪细胞置换而导致肌纤维脱落。尽管内源性卫星细胞不断进行肌纤维再生，但这些事件却蒸蒸日上并取得进展。促炎性细胞因子转化生长因子-β（TGF-β）调节了对肌肉损伤/疾病的变性/再生反应，它还可以通过增加促纤维化蛋白（例如基质细胞蛋白骨膜素）的分泌来深刻影响细胞外基质的组成。 。在这里，我们显示骨膜蛋白的上调和分泌是病理性的，并在肌肉营养不良（MD）的δ-糖聚糖无效（Sgccd〜（-/-））小鼠模型中增强疾病。确实，缺少Postn基因的MD小鼠骨骼肌结构和功能显着改善。从机制上讲，Postn基因缺失改变了TGF-β信号传导，因此它现在以降低的纤维化水平增强了组织再生。 TGF-β与中和性单克隆抗体的系统拮抗作用减轻了体内Postn缺失的有益作用。这些数据表明，骨膜素通过促进/允许TGF-β的病理作用而在MD中起疾病决定因素的作用，表明骨膜素的抑制可以代表独特的治疗方法。

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