Cellular Communication Network Factor 2, CCN2, is a profibrotic cytokine implicated in physiological and pathological processes in mammals. The expression of CCN2 is markedly increased in dystrophic muscles. Interestingly, diminishing CCN2 genetically or inhibiting its function improves the phenotypes of chronic muscular fibrosis in rodent models. Elucidating the cell-specific mechanisms behind the induction of CCN2 is a fundamental step in understanding its relevance in muscular dystrophies. Here, we show that the small lipids LPA and 2S-OMPT induce CCN2 expression in fibro/adipogenic progenitors (FAPs) through the activation of the LPA receptor and, to a lower extent, by also the LPA receptor. These cells show a stronger induction than myoblasts or myotubes. We show that the LPA/LPARs axis requires ROCK kinase activity and organized actin cytoskeleton upstream of YAP/TAZ signaling effectors to upregulate CCN2 levels, suggesting that mechanical signals are part of the mechanism behind this process. In conclusion, we explored the role of the LPA/LPAR axis on CCN2 expression, showing a strong cytoskeletal-dependent response in muscular FAPs.

中文翻译：

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LPA 诱导的肌肉纤维/脂肪祖细胞 (FAP) 中 CCN2 的表达：揭示细胞通讯网络

细胞通讯网络因子 2 (CCN2) 是一种促纤维化细胞因子，与哺乳动物的生理和病理过程有关。 CCN2 的表达在营养不良的肌肉中显着增加。有趣的是，从基因上减少 CCN2 或抑制其功能可以改善啮齿动物模型中慢性肌肉纤维化的表型。阐明 CCN2 诱导背后的细胞特异性机制是了解其与肌营养不良症相关性的基本步骤。在这里，我们表明，小脂质 LPA 和 2S-OMPT 通过激活 LPA 受体，并在较低程度上通过 LPA 受体，诱导纤维/脂肪祖细胞 (FAP) 中的 CCN2 表达。这些细胞表现出比成肌细胞或肌管更强的诱导作用。我们发现 LPA/LPAR 轴需要 YAP/TAZ 信号效应器上游的 ROCK 激酶活性和有组织的肌动蛋白细胞骨架来上调 CCN2 水平，这表明机械信号是该过程背后机制的一部分。总之，我们探索了 LPA/LPAR 轴对 CCN2 表达的作用，显示出肌肉 FAP 中强烈的细胞骨架依赖性反应。