Department of Medicine, Division of Rheumatology, Medical University of South Carolina, Charleston, USA.
Division of Plastic Surgery, University of North Carolina, Chapel Hill, USA.
Arthritis Res Ther. 2021 Feb 27;23(1):68. doi: 10.1186/s13075-021-02441-x.
Both TGFβ and estradiol (E2), a form of estrogen, are pro-fibrotic in the skin. In the connective tissue disease, systemic sclerosis (SSc), both TGFβ and E2 are likely pathogenic. Yet the regulation of TGFβ in E2-induced dermal fibrosis remains ill-defined. Elucidating those regulatory mechanisms will improve the understanding of fibrotic disease pathogenesis and set the stage for developing potential therapeutics. Using E2-stimulated primary human dermal fibroblasts in vitro and human skin tissue ex vivo, we identified the important regulatory proteins for TGFβ and investigated the extracellular matrix (ECM) components that are directly stimulated by E2-induced TGFβ signaling.
We used primary human dermal fibroblasts in vitro and human skin tissue ex vivo stimulated with E2 or vehicle (ethanol) to measure TGFβ1 and TGFβ2 levels using quantitative PCR (qPCR). To identify the necessary cell signaling proteins in E2-induced TGFβ1 and TGFβ2 transcription, human dermal fibroblasts were pre-treated with an inhibitor of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway, U0126. Finally, human skin tissue ex vivo was pre-treated with SB-431542, a TGFβ receptor inhibitor, and ICI 182,780, an estrogen receptor α (ERα) inhibitor, to establish the effects of TGFβ and ERα signaling on E2-induced collagen 22A1 (Col22A1) transcription.
We found that expression of TGFβ1, TGFβ2, and Col22A1, a TGFβ-responsive gene, is induced in response to E2 stimulation. Mechanistically, Col22A1 induction was blocked by SB-431542 and ICI 182,780 despite E2 stimulation. Additionally, inhibiting E2-induced ERK/MAPK activation and early growth response 1 (EGR1) transcription prevents the E2-induced increase in TGFβ1 and TGFβ2 transcription and translation.
We conclude that E2-induced dermal fibrosis occurs in part through induction of TGFβ1, 2, and Col22A1, which is regulated through EGR1 and the MAPK pathway. Thus, blocking estrogen signaling and/or production may be a novel therapeutic option in pro-fibrotic diseases.
转化生长因子-β（TGFβ）和雌激素（E2）都能促进皮肤纤维化。在结缔组织疾病系统性硬化症（SSc）中，TGFβ和 E2 都可能具有致病性。然而，E2 诱导的真皮纤维化中 TGFβ的调节仍不明确。阐明这些调节机制将有助于加深对纤维化疾病发病机制的理解，并为开发潜在的治疗方法奠定基础。我们使用体外 E2 刺激的原代人真皮成纤维细胞和人皮肤组织，鉴定了 TGFβ和 EGR1 表达的重要调节蛋白，并研究了 ECM 成分直接受 E2 诱导的 TGFβ信号刺激的情况。
我们使用体外 E2 或载体（乙醇）刺激的原代人真皮成纤维细胞和人皮肤组织，通过 qPCR 测量 TGFβ1 和 TGFβ2 水平。为了鉴定 E2 诱导的 TGFβ1 和 TGFβ2 转录中必需的细胞信号蛋白，我们用细胞外信号调节激酶/丝裂原活化蛋白激酶（ERK/MAPK）通路抑制剂 U0126 预处理人真皮成纤维细胞。最后，我们用 TGFβ 受体抑制剂 SB-431542 和雌激素受体 α（ERα）抑制剂 ICI 182,780 预处理人皮肤组织，以确定 TGFβ 和 ERα 信号对 E2 诱导的 Col22A1（编码胶原 22A1）转录的影响。
我们发现 TGFβ1、TGFβ2 和 Col22A1（TGFβ 反应基因）的表达在 E2 刺激后被诱导。从机制上讲，尽管有 E2 刺激，但 SB-431542 和 ICI 182,780 阻断了 Col22A1 的诱导。此外，抑制 E2 诱导的 ERK/MAPK 激活和早期生长反应 1（EGR1）转录可防止 E2 诱导的 TGFβ1 和 TGFβ2 转录和翻译增加。
我们得出结论，E2 诱导的真皮纤维化部分是通过诱导 TGFβ1、2 和 Col22A1 发生的，而 Col22A1 的调节是通过 EGR1 和 MAPK 途径进行的。因此，阻断雌激素信号和/或产生可能是抗纤维化疾病的一种新的治疗选择。
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