Yin/Yang expression of CCN family members: Transforming growth factor beta 1, via ALK5/FAK/MEK, induces CCN1 and CCN2, yet suppresses CCN3, expression in human dermal fibroblasts
Yin/Yang expression of CCN family members: Transforming growth factor beta 1, via ALK5/FAK/MEK, induces CCN1 and CCN2, yet suppresses CCN3, expression in human dermal fibroblasts
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DOI：
10.1371/journal.pone.0218178
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发表时间：
2019-06
期刊：
影响因子：
3.7
通讯作者：
Alexander Peidl;B. Perbal;A. Leask
中科院分区：
文献类型：
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作者：
Alexander Peidl;B. Perbal;A. Leask
微环境在驱动结缔组织疾病中的作用越来越受到重视。CCN家族的基质细胞蛋白是由细胞分泌到细胞外基质微环境中的信号传导调节剂，在细胞外基质微环境中，它们对器官发育、稳态和疾病具有深刻的背景依赖性影响。事实上，CCN蛋白是治疗干预的紧急靶标。最近的证据表明，在体内，CCN 3具有对抗CCN 2的作用。此外，当CCN 3表达高时，CCN 2表达低。也就是说，它们似乎以阴/阳的方式进行调节，从而导致CCN 2：CCN 3比率对控制组织稳态很重要的假设。为了开始检验CCN 2：CCN 3表达的改变在体内皮肤生物学中可能是重要的这一假设，我们评估了促纤维化蛋白TGF β 1对真皮成纤维细胞对CCN 3和CCN 2以及相关蛋白CCN 1的蛋白和RNA表达的相对离体影响。我们还使用信号转导抑制剂来开始鉴定控制成纤维细胞对TGF β 1应答能力的信号转导途径。正如预期的那样，CCN 1和CCN 2蛋白和mRNA在人皮肤成纤维细胞中由TGF β 1诱导。这种诱导被TAK 1、FAK、YAP 1和MEK抑制剂阻断。相反，TGF β 1以对FAK、MEK、TAK 1或YAP 1抑制不敏感的方式抑制CCN 3 mRNA表达。出乎意料的是，在人真皮成纤维细胞中基本上没有检测到CCN 3蛋白。这些数据表明，在真皮成纤维细胞中，促纤维化蛋白TGF β 1在mRNA和蛋白质水平上对CCN 3相对于CCN 2和CCN 1具有不同的作用。鉴于CCN蛋白在体内皮肤中的主要来源是成纤维细胞，我们的数据一致，即响应于促纤维化剂如TGF β 1的CCN 2/CCN 1：CCN 3比率的改变可能在结缔组织病理学（包括纤维化）中起作用。
The role of the microenvironment in driving connective tissue disease is being increasingly appreciated. Matricellular proteins of the CCN family are signaling modifiers that are secreted by cells into the extracellular matrix microenvironment where they have profound, context-dependent effects on organ development, homeostasis and disease. Indeed, CCN proteins are emergent targets for therapeutic intervention. Recent evidence suggests that, in vivo, CCN3 has effects opposing CCN2. Moreover, when CCN3 expression is high, CCN2 expression is low. That is, they appear to be regulated in a yin/yang fashion, leading to the hypothesis that the CCN2:CCN3 ratio is important to control tissue homeostasis. To begin to test the hypothesis that alterations in CCN2:CCN3 expression might be important in skin biology in vivo, we evaluated the relative ex vivo effects of the profibrotic protein TGFbeta1 on dermal fibroblasts on protein and RNA expression of CCN3 and CCN2, as well as the related protein CCN1. We also used signal transduction inhibitors to begin to identify the signal transduction pathways controlling the ability of fibroblasts to respond to TGFbeta1. As anticipated, CCN1 and CCN2 protein and mRNA were induced by TGFbeta1 in human dermal fibroblasts. This induction was blocked by TAK1, FAK, YAP1 and MEK inhibition. Conversely, TGFbeta1 suppressed CCN3 mRNA expression in a fashion insensitive to FAK, MEK, TAK1 or YAP1 inhibition. Unexpectedly, CCN3 protein was not detected in human dermal fibroblasts basally. These data suggest that, in dermal fibroblasts, the profibrotic protein TGFbeta1 has a divergent effect on CCN3 relative to CCN2 and CCN1, both at the mRNA and protein level. Given that the major source in skin in vivo of CCN proteins are fibroblasts, our data are consistent that alterations in CCN2/CCN1: CCN3 ratios in response to profibrotic agents such as TGFbeta1 may play a role in connective tissue pathologies including fibrosis.