Jefferson Institute of Molecular Medicine and Scleroderma Center.
Department of Orthopedic Surgery Research, Thomas Jefferson University, Philadelphia.
Rheumatology (Oxford). 2020 Oct 1;59(10):3092-3098. doi: 10.1093/rheumatology/keaa200.
SSc is a systemic fibrotic disease affecting skin, numerous internal organs and the microvasculature. The molecular pathogenesis of SSc tissue fibrosis has not been fully elucidated, although TGF-β1 plays a crucial role. The Hic-5 protein encoded by the TGF-β1-inducible HIC-5 gene participates in numerous TGF-β-mediated pathways, however, the role of Hic-5 in SSc fibrosis has not been investigated. The aim of this study was to examine HIC-5 involvement in SSc tissue fibrosis.
Affected skin from three patients with diffuse SSc and dermal fibroblasts cultured from affected and non-affected SSc skin were examined for HIC-5 and COL1A1 gene expression. Real-time PCR, IF microscopy, western blotting and small interfering RNA-mediated HIC-5 were performed.
HIC-5 and COL1A1 transcripts and Hic-5, type 1 collagen (COL1) and α-smooth muscle actin (α-SMA) protein levels were increased in clinically affected SSc skin compared with normal skin and in cultured dermal fibroblasts from affected SSc skin compared with non-affected skin fibroblasts from the same patients. HIC-5 knockdown caused a marked reduction of COL1 production in SSc dermal fibroblasts.
HIC-5 expression is increased in affected SSc skin compared with skin from normal individuals. Affected SSc skin fibroblasts display increased HIC-5 and COL1A1 expression compared with non-affected skin fibroblasts from the same patients. Hic-5 protein was significantly increased in cultured SSc dermal fibroblasts. HIC-5 mRNA knockdown in SSc fibroblasts caused >50% reduction of COL1 production. Although these are preliminary results owing to the small number of skin samples studied, they indicate that Hic-5 plays a role in the profibrotic activation of SSc dermal fibroblasts and may represent a novel molecular target for antifibrotic therapy in SSc.
SSc 是一种影响皮肤、许多内部器官和微血管系统的系统性纤维化疾病。虽然 TGF-β1 起着至关重要的作用，但 SSc 组织纤维化的分子发病机制尚未完全阐明。TGF-β1 诱导的 HIC-5 基因编码的 Hic-5 蛋白参与了许多 TGF-β 介导的途径，然而，Hic-5 在 SSc 纤维化中的作用尚未被研究。本研究旨在探讨 Hic-5 与 SSc 组织纤维化的关系。
检测了 3 例弥漫性 SSc 患者的病变皮肤和来源于病变和非病变 SSc 皮肤的真皮成纤维细胞中 HIC-5 和 COL1A1 基因的表达。进行了实时 PCR、IF 显微镜、western 印迹和小干扰 RNA 介导的 HIC-5 实验。
与正常皮肤相比，临床病变 SSc 皮肤中的 HIC-5 和 COL1A1 转录物以及 Hic-5、I 型胶原蛋白（COL1）和α-平滑肌肌动蛋白（α-SMA）蛋白水平均升高，与来自同一患者的非病变 SSc 皮肤成纤维细胞相比，来源于病变 SSc 皮肤的成纤维细胞中 HIC-5 和 COL1A1 转录物以及 Hic-5、COL1 和α-SMA 蛋白水平均升高。在 SSc 真皮成纤维细胞中，HIC-5 敲低导致 COL1 产生明显减少。
与正常个体的皮肤相比，病变 SSc 皮肤中的 HIC-5 表达增加。与同一患者的非病变皮肤成纤维细胞相比，病变 SSc 皮肤成纤维细胞中 HIC-5 和 COL1A1 的表达增加。Hic-5 蛋白在培养的 SSc 真皮成纤维细胞中显著增加。SSc 成纤维细胞中 HIC-5mRNA 的敲低导致 COL1 产生减少了>50%。尽管由于研究的皮肤样本数量较少，这些结果只是初步的，但它们表明 Hic-5 在 SSc 真皮成纤维细胞的促纤维化激活中起作用，可能成为 SSc 抗纤维化治疗的新分子靶点。
