Department of Ophthalmology, Third Xiangya Hospital, Central South University, Changsha, 410013, China.
Department of Ophthalmology, Third Xiangya Hospital, Central South University, Changsha, 410013, China.
Mol Cell Endocrinol. 2023 Jan 1;559:111780. doi: 10.1016/j.mce.2022.111780. Epub 2022 Sep 27.
Molecular pathways that contribute to orbital fibroblast activation during thyroid-eye disease (TED) may promote TED progression. Non-coding RNAs, especially miRNAs, play a critical role in the pathogenesis of TED. In the present study, miR-103a-3p was dramatically upregulated and TGFBR3 was downregulated within TED orbital tissue samples and TGF-β-stimulated TED orbital fibroblasts. miR-103a-3p inhibition in TGF-β-stimulated TED orbital fibroblasts partially abolished TGF-β-induced fibrotic alterations, as manifested by the impaired fibroblast cell viability and decreased vimentin and fibronectin levels. miR-103a-3p directly targeted TGFBR3 in TED orbital samples and TGF-β-stimulated TED orbital fibroblasts. In TGF-β-stimulated TED orbital fibroblasts, TGFBR3 overexpression inhibited fibroblast cell viability and decreased vimentin and fibronectin levels. TGFBR3 overexpression partially attenuated the inhibitory effects of miR-103a-3p overexpression on TGFBR3 expression and the promotive effects of miR-103a-3p overexpression on TGF-β-induced fibrotic alterations. Under TGF-β stimulation, miR-103a-3p overexpression significantly promoted, whereas TGFBR3 overexpression inhibited the phosphorylation of Erk1/2, JNK, Smad2, and Smad3. TGFBR3 overexpression also partially abolished the effects of miR-103a-3p overexpression on Erk1/2, JNK, Smad2, and Smad3 phosphorylation. In conclusion, the miR-103a-3p/TGFBR3 axis regulated TGF-β-induced TED orbital fibroblast activation and fibrosis in TED, with the possible involvement of the Erk/JNK and TGF-β/Smad signaling pathways.
导致甲状腺眼病（TED）期间眼眶成纤维细胞激活的分子途径可能促进 TED 的进展。非编码 RNA，尤其是 miRNA，在 TED 的发病机制中发挥着关键作用。在本研究中，miR-103a-3p 在 TED 眼眶组织样本和 TGF-β 刺激的 TED 眼眶成纤维细胞中显著上调，而 TGFBR3 下调。在 TGF-β 刺激的 TED 眼眶成纤维细胞中，抑制 miR-103a-3p 部分消除了 TGF-β 诱导的纤维化改变，表现为成纤维细胞活力受损和波形蛋白和纤连蛋白水平降低。miR-103a-3p 在 TED 眼眶样本和 TGF-β 刺激的 TED 眼眶成纤维细胞中直接靶向 TGFBR3。在 TGF-β 刺激的 TED 眼眶成纤维细胞中，TGFBR3 过表达抑制成纤维细胞活力并降低波形蛋白和纤连蛋白水平。TGFBR3 过表达部分减弱了 miR-103a-3p 过表达对 TGFBR3 表达的抑制作用和 miR-103a-3p 过表达对 TGF-β 诱导的纤维化改变的促进作用。在 TGF-β 刺激下，miR-103a-3p 过表达显著促进，而 TGFBR3 过表达抑制 Erk1/2、JNK、Smad2 和 Smad3 的磷酸化。TGFBR3 过表达也部分消除了 miR-103a-3p 过表达对 Erk1/2、JNK、Smad2 和 Smad3 磷酸化的影响。总之，miR-103a-3p/TGFBR3 轴调节 TGF-β 诱导的 TED 眼眶成纤维细胞激活和纤维化，可能涉及 Erk/JNK 和 TGF-β/Smad 信号通路。
