皮肤纤维化是系统性硬化症(SSc)的常见病理表现,瘢痕疙瘩,和局部硬皮病(LS)的特征是成纤维细胞活化和过度的细胞外基质(ECM)沉积。然而,由于其机制尚不清楚,很少有有效的药物可用于治疗皮肤纤维化。在我们的研究中,我们重新分析了白种人的皮肤RNA测序数据,非洲,和来自基因表达综合(GEO)数据库的西班牙裔SSc患者。我们发现粘着斑途径上调,Zyxin似乎是参与皮肤纤维化的主要粘着斑蛋白,并进一步验证了其在几种纤维化疾病中国人皮肤组织中的表达,包括SSc,瘢痕疙瘩,和LS。此外,我们发现Zyxin抑制可以使用Zyxin敲低和敲除小鼠显着减轻皮肤纤维化,人瘢痕疙瘩裸鼠模型和皮肤外植体。双重免疫荧光染色显示Zyxin在成纤维细胞中高表达。进一步分析显示,在Zyxin过表达的成纤维细胞中,促纤维化基因表达和胶原蛋白产生增加,在Zyxin干扰的SSc成纤维细胞中减少。此外,转录组和细胞培养分析显示,Zyxin抑制可以通过整合素调节FAK/PI3K/AKT和TGF-β信号通路有效减轻皮肤纤维化。这些结果表明Zyxin似乎是皮肤纤维化的潜在新治疗靶标。
Skin fibrosis is a common pathological manifestation in systemic sclerosis (SSc), keloid, and localized scleroderma (LS) characterized by fibroblast activation and excessive extracellular matrix (ECM) deposition. However, few effective drugs are available to treat skin fibrosis due to its unclear mechanisms. In our study, we reanalyzed skin RNA-sequencing data of Caucasian, African, and Hispanic SSc patients from the Gene Expression Omnibus (GEO) database. We found that the focal adhesion pathway was up-regulated and
Zyxin appeared to be the primary focal adhesion protein involved in skin fibrosis, and we further verified its expression in Chinese skin tissues of several fibrotic diseases, including SSc, keloid, and LS. Moreover, we found
Zyxin inhibition could significantly alleviate skin fibrosis using
Zyxin knock-down and knock-out mice, nude mouse model and skin explants of human keloid. Double immunofluorescence staining showed that
Zyxin was highly expressed in fibroblasts. Further analysis revealed pro-fibrotic gene expression and collagen production increased in Zyxin over-expressed fibroblasts, and decreased in
Zyxin interfered SSc fibroblasts. In addition, transcriptome and cell culture analyses revealed Zyxin inhibition could effectively attenuate skin fibrosis by regulating the FAK/PI3K/AKT and TGF-β signaling pathways via integrins. These results suggest
Zyxin appears a potential new therapeutic target for skin fibrosis.