Abstract：
As persistent elevation of transforming growth factor-β (TGF-β) promotes fibrosis of muscles and joints and accelerates disease progression in amyotrophic lateral sclerosis (ALS), we investigated whether inhibition of TGF-β would be effective against both exacerbations. The effects of TGF-β and its inhibitor on myoblasts and fibroblasts were tested in vitro and confirmed in vivo, and the dual action of a TGF-β inhibitor in ameliorating the pathogenic role of TGF-β in ALS mice was identified. In the peripheral neuromuscular system, fibrosis in the muscles and joint cavities induced by excessive TGF-β causes joint contracture and muscular degeneration, which leads to motor dysfunction. In an ALS mouse model, an increase in TGF-β in the central nervous system (CNS), consistent with astrocyte activity, was associated with M1 microglial activity and pro-inflammatory conditions, as well as with neuronal cell death. Treatment with the TGF-β inhibitor halofuginone could prevent musculoskeletal fibrosis, resulting in the alleviation of joint contracture and delay of motor deterioration in ALS mice. Halofuginone could also reduce glial cell-induced neuroinflammation and neuronal apoptosis. These dual therapeutic effects on both the neuromuscular system and the CNS were observed from the beginning to the end stages of ALS; as a result, treatment with a TGF-β inhibitor from the early stage of disease delayed the time of symptom exacerbation in ALS mice, which led to prolonged survival.
摘要：
由于转化生长因子-β（TGF-β）的持续升高促进肌萎缩侧索硬化症（ALS）的肌肉和关节纤维化并加速疾病进展，我们研究了抑制TGF-β是否对两种加重均有效.体外检测TGF-β及其抑制剂对成肌细胞和成纤维细胞的作用,并确定了TGF-β抑制剂在改善ALS小鼠中TGF-β的致病作用中的双重作用。在周围神经肌肉系统中，过度TGF-β诱导的肌肉和关节腔纤维化导致关节挛缩和肌肉变性，导致运动障碍.在ALS小鼠模型中,中枢神经系统（CNS）中TGF-β的增加，与星形胶质细胞活性一致，与M1小胶质细胞活性和促炎状态有关，以及神经元细胞死亡。用TGF-β抑制剂卤夫酮治疗可以预防肌肉骨骼纤维化，从而减轻ALS小鼠的关节挛缩和延缓运动恶化。卤夫酮还可以减少神经胶质细胞诱导的神经炎症和神经元凋亡。这些对神经肌肉系统和中枢神经系统的双重治疗作用观察到从开始到结束阶段的ALS;因此,从疾病的早期阶段用TGF-β抑制剂治疗可延迟ALS小鼠症状加重的时间，这导致了长期的生存。
