TWEAK/Fn14, a pathway and novel therapeutic target in myotonic dystrophy.
TWEAK/Fn14, a pathway and novel therapeutic target in myotonic dystrophy.
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DOI：
10.1093/hmg/ddu617
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发表时间：
2015-04
影响因子：
3.5
通讯作者：
R. S. Yadava;Erin P. Foff;Qing Yu;J. Gladman;Y. Kim;K. Bhatt;C. Thornton;T. Zheng;M. Mahadevan
中科院分区：
文献类型：
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作者：
R. S. Yadava;Erin P. Foff;Qing Yu;J. Gladman;Y. Kim;K. Bhatt;C. Thornton;T. Zheng;M. Mahadevan
强直性肌营养不良 1 型 (DM1) 是成人中最常见的肌营养不良症，其特征是进行性肌肉萎缩和多系统并发症。 DM1 是 RNA 毒性引起的疾病的原型。目前尚无治疗方法。在这里，我们确定了成纤维细胞生长因子诱导型 14 (Fn14)（肿瘤坏死因子受体超家族的成员）在 RNA 毒性小鼠模型的骨骼肌和心脏以及 DM1 患者的组织中被诱导，并且其表达与肌肉病理学的严重程度相关。这与通过 NF-κB 途径的下游信号传导有关。在具有 RNA 毒性的小鼠中，Fn14 基因缺失可减少肌肉病理并改善功能。重要的是，用抗 TWEAK 抗体阻断 TWEAK/Fn14 信号传导同样可以改善受影响小鼠的肌肉组织病理学和功能结果。这些结果揭示了治疗开发的新途径，并为新的治疗靶点提供了概念证明，该靶点的临床可用疗法可潜在治疗 DM1 型肌营养不良症。
Myotonic dystrophy type 1 (DM1), the most prevalent muscular dystrophy in adults, is characterized by progressive muscle wasting and multi-systemic complications. DM1 is the prototype for disorders caused by RNA toxicity. Currently, no therapies exist. Here, we identify that fibroblast growth factor-inducible 14 (Fn14), a member of the tumor necrosis factor receptor super-family, is induced in skeletal muscles and hearts of mouse models of RNA toxicity and in tissues from DM1 patients, and that its expression correlates with severity of muscle pathology. This is associated with downstream signaling through the NF-κB pathways. In mice with RNA toxicity, genetic deletion of Fn14 results in reduced muscle pathology and better function. Importantly, blocking TWEAK/Fn14 signaling with an anti-TWEAK antibody likewise improves muscle histopathology and functional outcomes in affected mice. These results reveal new avenues for therapeutic development and provide proof of concept for a novel therapeutic target for which clinically available therapy exists to potentially treat muscular dystrophy in DM1.