Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Hunan Key Laboratory of Medical Epigenetics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.; Department of Medical Genetics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Hunan Key Laboratory of Medical Epigenetics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
Int Immunopharmacol. 2023 Aug;121:110420. doi: 10.1016/j.intimp.2023.110420. Epub 2023 Jun 16.
Systemic sclerosis (SSc) is an autoimmune connective tissue disease that leads to irreversible fibrosis of the skin and the internal organs. The etiology of SSc is complex, its pathophysiology is poorly understood, and clinical therapeutic options are restricted. Thus, research into medications and targets for treating fibrosis is essential and urgent. Fos-related antigen 2 (Fra2) is a transcription factor that is a member of the activator protein-1 family. Fra2 transgenic mice were shown to have spontaneous fibrosis. All-trans retinoic acid (ATRA) is a vitamin A intermediate metabolite and ligand for the retinoic acid receptor (RAR), which possesses anti-inflammatory and anti-proliferative properties. Recent research has demonstrated that ATRA also has an anti-fibrotic effect. However, the exact mechanism is not fully understood. Interestingly, we identified potential binding sites for the transcription factor RARα to the promoter region of the FRA2 gene through JASPAR and PROMO databases. In this study, the pro-fibrotic effect of Fra2 in SSc is confirmed. SSc dermal fibroblasts and bleomycin-induced fibrotic tissues of SSc animals exhibit increased levels of Fra2. Inhibition of Fra2 expression in SSc dermal fibroblasts with Fra2 siRNA markedly decreased collagen I expression. ATRA reduced the expressions of Fra2, collagen I, and α-smooth muscle actin(α-SMA) in SSc dermal fibroblasts and bleomycin-induced fibrotic tissues of SSc mice. In addition, chromatin immunoprecipitation and dual-luciferase assays demonstrated that retinoic acid receptor RARα binds to the FRA2 promoter and modulates its transcriptional activity. ATRA decreases collagen I expression both in vivo and in vitro via the reduction of Fra2 expression. This work establishes the rationale for expanding the use of ATRA in the treatment of SSc and indicates that Fra2 can be used as an anti-fibrotic target.
系统性硬化症（SSc）是一种自身免疫性结缔组织疾病，可导致皮肤和内脏器官的不可逆纤维化。SSc 的病因复杂，其病理生理学尚未完全阐明，临床治疗选择有限。因此，研究纤维化的药物和靶点至关重要且紧迫。Fos 相关抗原 2（Fra2）是一种转录因子，属于激活蛋白-1 家族的成员。Fra2 转基因小鼠表现出自发性纤维化。全反式视黄酸（ATRA）是维生素 A 的中间代谢产物，也是视黄酸受体（RAR）的配体，具有抗炎和抗增殖作用。最近的研究表明，ATRA 还具有抗纤维化作用。然而，确切的机制尚不完全清楚。有趣的是，我们通过 JASPAR 和 PROMO 数据库确定了转录因子 RARα 到 Fra2 基因启动子区域的潜在结合位点。在这项研究中，证实了 Fra2 在 SSc 中的促纤维化作用。SSc 皮肤成纤维细胞和 SSc 动物的博来霉素诱导的纤维化组织中 Fra2 水平升高。Fra2siRNA 抑制 SSc 皮肤成纤维细胞中的 Fra2 表达可显著降低胶原 I 的表达。ATRA 降低了 SSc 皮肤成纤维细胞和 SSc 小鼠博来霉素诱导的纤维化组织中 Fra2、胶原 I 和α-平滑肌肌动蛋白（α-SMA）的表达。此外，染色质免疫沉淀和双荧光素酶报告基因检测表明，维甲酸受体 RARα 结合 Fra2 启动子并调节其转录活性。ATRA 通过降低 Fra2 表达在体内和体外均降低胶原 I 的表达。这项工作为扩大 ATRA 在 SSc 治疗中的应用提供了依据，并表明 Fra2 可作为抗纤维化的靶点。
