The inhibition of CTGF/CCN2 activity improves muscle and locomotor function in a murine ALS model
The inhibition of CTGF/CCN2 activity improves muscle and locomotor function in a murine ALS model
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DOI：
10.1093/hmg/ddy204
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发表时间：
2018-08-15
影响因子：
3.5
通讯作者：
Brandan, Enrique
中科院分区：
文献类型：
--
作者：
Gonzalez, David;Rebolledo, Daniela L.;Brandan, Enrique
肌萎缩侧索硬化症（ALS）是一种毁灭性的成人发病的进行性神经退行性疾病，其特征是上、下运动神经元变性。总共 20% 的家族性 ALS (fALS) 病例是由超氧化物歧化酶 1 (SOD1) 突变引起的。尽管自第一个 ALS 小鼠模型产生以来已经过去了 20 多年，但 ALS 发病机制的精确分子机制仍然未知。 CTGF/CCN2 是一种具有相关纤维化活性的基质细胞蛋白，在多种慢性疾病中表达上调。使用单克隆中和抗体 FG-3019 抑制 CTGF/CCN2 可减少多种慢性疾病的纤维化，包括 mdx 小鼠（杜氏肌营养不良症 (DMD) 的小鼠模型）。在这项工作中，我们发现 hSOD193A 小鼠的骨骼肌和脊髓中 CTGF/CCN2 水平升高。在这种情况下，我们证明 FG-3019 不仅可以减少 hSOD1G93A 小鼠骨骼肌纤维化，还可以改善肌肉和运动性能。我们证明 FG-3019 治疗可减少 hSOD1G93A 小鼠的肌肉萎缩。我们还发现神经肌肉接头 (NM) 神经支配得到改善，坐骨神经髓磷脂变性减少，这表明 FG-3019 治疗的 hSOD1G93A 小鼠中神经肌肉通讯的改变得到部分改善。此外，我们还发现 CTGF/CCN2 在星形胶质细胞和神经元中表达，主要在有症状的 hSOD1G93A 小鼠的脊髓背侧区域。总之，这些结果表明 CTGF/CCN2 可能是改善 ALS 患者症状和提高生活质量的新治疗靶点。
Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset progressive neurodegenerative disease characterized by upper and lower motoneuron degeneration. A total of 20% of familial ALS (fALS) cases are explained by mutations in the superoxide dismutase 1 (SOD1) enzyme. Although more than 20 years have passed since the generation of the first ALS mouse model, the precise molecular mechanisms of ALS pathogenesis remain unknown. CTGF/CCN2 is a matricellular protein with associated fibrotic activity that is up-regulated in several chronic diseases. The inhibition of CTGF/CCN2 with the monoclonal neutralizing antibody FG-3019 reduces fibrosis in several chronic disorders including the mdx mice, a murine model for Duchenne muscular dystrophy (DMD). In this work, we show that there are increased levels of CTGF/CCN2 in skeletal muscle and spinal cord of hSOD193A mice. In this scenario, we show evidence that FG-3019 not only reduces fibrosis in skeletal muscle of hSOD1G93A mice, but also improves muscle and locomotor performance. We demonstrate that treatment with FG-3019 reduces muscle atrophy in hSOD1G93A mice. We also found improvement of neuromuscular junction (NM)) innervation together with a reduction in myelin degeneration in the sciatic nerve, suggesting that alterations in nerve-muscle communication are partially improved in FG-3019-treated hSOD1G93A mice. Moreover, we also found that CTGF/CCN2 is expressed in astrocytes and neurons, predominantly in dorsal areas of spinal cord from symptomatic hSOD1G93A mice. Together, these results reveal that CTGF/CCN2 might be a novel therapeutic target to ameliorate symptoms and improve the quality of life of ALS patients.