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Denervation-induced skeletal muscle fibrosis is mediated by CTGF/CCN2 independently of TGF-β.
Matrix Biology ( IF 4.5 ) Pub Date : 2019-02-01 , DOI: 10.1016/j.matbio.2019.01.002
Daniela L Rebolledo 1 , David González 2 , Jennifer Faundez-Contreras 2 , Osvaldo Contreras 2 , Carlos P Vio 3 , Joanne E Murphy-Ullrich 4 , Kenneth E Lipson 5 , Enrique Brandan 2
Affiliation  

Muscular fibrosis is caused by excessive accumulation of extracellular matrix (ECM) that replaces functional tissue, and it is a feature of several myopathies and neuropathies. Knowledge of the biology and regulation of pro-fibrotic factors is critical for the development of new therapeutic strategies. Upon unilateral sciatic nerve transection, we observed accumulation of ECM proteins such as collagen and fibronectin in the denervated hindlimb, together with increased levels of the profibrotic factors transforming growth factor type β (TGF-β) and connective tissue growth factor (CTGF/CCN2). In mice hemizygous for CTGF/CCN2 or in mice treated with a blocking antibody against CTGF/CCN2, we observed reduced accumulation of ECM proteins after denervation as compared to control mice, with no changes in fibro/adipogenic progenitors (FAPs), suggesting a direct role of CTGF/CCN2 on denervation-induced fibrosis. During time course experiments, we observed that ECM proteins and CTGF/CCN2 levels are increased early after denervation (2-4 days), while TGF-β signaling shows a delayed kinetics of appearance (1-2 weeks). Furthermore, blockade of TGF-β signaling does not decrease fibronectin or CTGF levels after 4 days of denervation. These results suggest that in our model CTGF/CCN2 is not up-regulated by canonical TGF-β signaling early after denervation and that other factors are likely involved in the early fibrotic response following skeletal muscle denervation.

中文翻译:

去神经引起的骨骼肌纤维化是由CTGF / CCN2介导的,与TGF-β无关。

肌纤维化是由细胞外基质(ECM)的过度积累引起的,该细胞外基质替代了功能组织,这是多种肌病和神经病的特征。生物学知识和促纤维化因子的调控对于开发新的治疗策略至关重要。单侧坐骨神经横切后,我们观察到了失神经的后肢中ECM蛋白(如胶原蛋白和纤连蛋白)的积累,以及转化生长因子β(TGF-β)和结缔组织生长因子(CTGF / CCN2)的纤维化因子水平的升高。在对CTGF / CCN2半合子的小鼠中或在用针对CTGF / CCN2的封闭抗体治疗的小鼠中,我们观察到与对照小鼠相比,去神经后ECM蛋白的积聚减少,而纤维/脂肪形成祖细胞(FAP)没有变化,提示CTGF / CCN2在失神经引起的纤维化中具有直接作用。在时程实验中,我们观察到去神经后(2-4天)早期,ECM蛋白和CTGF / CCN2的水平增加,而TGF-β信号显示出延迟的外观动力学(1-2周)。此外,去神经化4天后,对TGF-β信号的阻断不会降低纤连蛋白或CTGF的水平。这些结果表明,在我们的模型中,CTGF / CCN2在失神经后早期并不受规范的TGF-β信号上调,而骨骼肌失神经后的早期纤维化反应也可能涉及其他因素。而TGF-β信号显示出出现动力学延迟(1-2周)。此外,去神经化4天后,对TGF-β信号的阻断不会降低纤连蛋白或CTGF的水平。这些结果表明,在我们的模型中,CTGF / CCN2在失神经后早期并不受规范的TGF-β信号上调,而骨骼肌失神经后的早期纤维化反应也可能涉及其他因素。而TGF-β信号显示出出现动力学延迟(1-2周)。此外,去神经化4天后,对TGF-β信号的阻断不会降低纤连蛋白或CTGF的水平。这些结果表明,在我们的模型中,CTGF / CCN2在失神经后早期并不受规范的TGF-β信号上调,而骨骼肌失神经后的早期纤维化反应也可能涉及其他因素。
更新日期:2019-11-18
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