Department of Rehabilitation Medicine, NYU Grossman School of Medicine, New York, NY, USA.
Department of Microbiology, NYU Grossman School of Medicine, New York, NY, USA.
Exp Cell Res. 2021 Aug 15;405(2):112681. doi: 10.1016/j.yexcr.2021.112681. Epub 2021 Jun 2.
Fibrosis of the vocal folds poses a substantive clinical challenge potentially underlying the rapid proliferation of direct steroid injections into the upper airway. The variable clinical response to glucocorticoids (GCs) in the vocal folds is likely related to diversity inherent to GCs and patient-specific, and upstream, cell-specific responses to GCs. Broadly, we hypothesize the disparity in clinical outcomes are due to undesirable effects of GCs on resident fibroblasts. Transcriptome analysis identified significant GC-mediated modulation of Hippo signaling, a known regulator of fibrotic gene expression. Subsequent analysis confirmed GC-mediated YAP activation, a transcriptional co-factor in the Hippo signaling pathway. YAP inhibition attenuated ACTA2 expression in GC-treated human vocal fold fibroblasts. Nuclear localization and phosphorylation at Ser211, however, was not affected by YAP inhibition, suggesting nuclear translocation of YAP is indirectly driven by GR. RNA-seq analysis confirmed the influence of GCs on Wnt signaling, and canonical Wnt signaling target genes were upregulated by GCs. These data implicate YAP and its downstream targets as putative mediators of a pro-fibrotic response to GCs. Therapeutic YAP inhibition may ultimately be clinically relevant and warrants further consideration.
声带纤维化构成实质性的临床挑战，可能是导致糖皮质激素（GCs）直接注射到气道的主要原因。GCs 在声带中的临床反应存在差异，这可能与 GC 的多样性以及患者特有的、上游的 GC 细胞特异性反应有关。我们广泛假设，临床结果的差异是由于 GC 对常驻成纤维细胞产生了不良影响。转录组分析确定了 Hippo 信号的显著 GC 介导调节，Hippo 信号是纤维化基因表达的已知调节剂。随后的分析证实了 GC 介导的 YAP 激活，这是 Hippo 信号通路中的转录共因子。YAP 抑制减弱了 GC 处理的人声带成纤维细胞中 ACTA2 的表达。然而，YAP 抑制并不影响 YAP 在 Ser211 处的核定位和磷酸化，这表明 YAP 的核易位是由 GR 间接驱动的。RNA-seq 分析证实了 GCs 对 Wnt 信号的影响，GCs 上调了经典 Wnt 信号靶基因。这些数据表明 YAP 及其下游靶标可能是 GC 诱导的促纤维化反应的潜在介质。YAP 的治疗性抑制最终可能具有临床相关性，值得进一步考虑。
