Department of Rheumatology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
J Clin Immunol. 2013 Aug;33(6):1100-9. doi: 10.1007/s10875-013-9896-z. Epub 2013 May 9.
Uncontrolled fibrosis in multiple organs is the main cause of death in systemic sclerosis (SSc), and transforming growth factor-β (TGF-β) activation plays a fundamental role in the process. Our previous study demonstrated that miR-21 was significantly up-regulated in SSc fibroblasts. Here, we found that TGF-β regulated the expression of miR-21 and fibrosis-related genes, and decreased Smad7 expression. Over-expression of miR-21 in fibroblasts decreased the levels of Smad7, whereas knockdown of miR-21 increased its expression. Further study using a reporter gene assay demonstrated Smad7 was a direct target of miR-21. Similar to human SSc, the expression of miR-21 increased in the bleomycin induced skin fibrosis. Inhibition of fibrosis by treatment with anti-fibrosis drug bortezomib restored the levels of miR-21 and Smad7. MiR-21 may function in an amplifying circuit to enhance TGF-β signaling events in SSc fibrosis, and suggesting that miR-21 may act as a potential therapeutic target.
多种器官不受控制的纤维化是全身性硬皮病（SSc）患者死亡的主要原因，而转化生长因子-β（TGF-β）的激活在这一过程中起着根本作用。我们之前的研究表明，miR-21 在 SSc 成纤维细胞中显著上调。在这里，我们发现 TGF-β 调节 miR-21 和纤维化相关基因的表达，并降低 Smad7 的表达。成纤维细胞中 miR-21 的过表达降低了 Smad7 的水平，而 miR-21 的敲低则增加了其表达。进一步使用报告基因检测证实 Smad7 是 miR-21 的直接靶标。类似于人类 SSc，miR-21 的表达在博来霉素诱导的皮肤纤维化中增加。用抗纤维化药物硼替佐米抑制纤维化恢复了 miR-21 和 Smad7 的水平。miR-21 可能在放大环路中发挥作用，增强 SSc 纤维化中的 TGF-β 信号事件，并提示 miR-21 可能作为一种潜在的治疗靶点。
