In healing tissue, fibroblasts differentiate to α-smooth muscle actin (SMA)-expressing contractile-myofibroblasts, which pull the wound edges together ensuring proper tissue repair. Uncontrolled expansion of the myofibroblast population may, however, lead to excessive tissue scarring and finally to organ dysfunction. Here, we demonstrate that the loss of low-density lipoprotein receptor-related protein (LRP) 1 overactivates the JNK1/2-c-Jun-Fra-2 signaling pathway leading to the induction of α-SMA and periostin expression in human lung fibroblasts (hLF). These changes are accompanied by increased contractility of the cells and the integrin- and protease-dependent release of active transforming growth factor (TGF)-β1 from the extracellular matrix (ECM) stores. Liberation of active TGF-β1 from the ECM further enhances α-SMA and periostin expression thus accelerating the phenotypic switch of hLF. Global gene expression profiling of LRP1-depleted hLF revealed that the loss of LRP1 affects cytoskeleton reorganization, cell-ECM contacts, and ECM production. In line with these findings, fibrotic changes in the skin and lung of Fra-2 transgenic mice were associated with LRP1 depletion and c-Jun overexpression. Altogether, our results suggest that dysregulation of LRP1 expression in fibroblasts in healing tissue may lead to the unrestrained expansion of contractile myofibroblasts and thereby to fibrosis development. Further studies identifying molecules, which regulate LRP1 expression, may provide new therapeutic options for largely untreatable human fibrotic diseases.

中文翻译：

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LRP1的丢失促进了收缩性肌成纤维细胞表型的获得和活性TGF-β1从ECM商店的释放。

在愈合组织中，成纤维细胞分化为表达α-平滑肌肌动蛋白（SMA）的收缩肌成纤维细胞，将伤口边缘拉在一起，确保正确的组织修复。然而，成肌纤维细胞群的不受控制的扩增可能导致过多的组织瘢痕形成并最终导致器官功能障碍。在这里，我们证明了低密度脂蛋白受体相关蛋白（LRP）1的丢失会过度激活JNK1 / 2-c-Jun-Fra-2信号通路，从而导致人肺成纤维细胞中α-SMA和骨膜素表达的诱导（hLF）。这些变化伴随着细胞收缩力的增加，以及从细胞外基质（ECM）储存区中整合素和蛋白酶依赖性的活性转化生长因子（TGF）-β1的释放。活性TGF-β1从ECM的释放进一步增强了α-SMA和骨膜素的表达，从而加速了hLF的表型转换。缺失LRP1的hLF的全局基因表达谱分析表明，LRP1的缺失影响细胞骨架重组，细胞ECM接触和ECM产生。与这些发现一致，Fra-2转基因小鼠的皮肤和肺纤维化改变与LRP1耗竭和c-Jun过表达有关。总而言之，我们的结果表明，愈合组织中成纤维细胞中LRP1表达的失调可能导致收缩性成纤维细胞无限制地扩张，从而导致纤维化发展。鉴定调节LRP1表达的分子的进一步研究可为很大程度上无法治疗的人类纤维化疾病提供新的治疗选择。