TGF-β1-induced connexin43 promotes scar formation via the Erk/MMP-1/collagen III pathway
TGF-β1-induced connexin43 promotes scar formation via the Erk/MMP-1/collagen III pathway
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DOI：
10.1111/joor.12829
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发表时间：
2020-11-01
影响因子：
2.9
通讯作者：
Liu, Yi
中科院分区：
文献类型：
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作者：
Li, Xiaoyan;Guo, Lijia;Liu, Yi
伤口愈合可以分为不同的阶段，这些阶段的及时启动和停止是伤口成功愈合的关键;否则，在受伤区域形成疤痕组织。连接蛋白（Cxs）被证实影响瘢痕形成，而Cx43，一个不可或缺的成员，被证明参与了这一过程。我们的研究探讨了Cx43在瘢痕形成中的调节作用和可能的细胞信号通路。建立了C57 BL/6 J小鼠口腔黏膜和皮肤创伤愈合模型。采用RT-PCR、Western blotting、免疫组化和免疫荧光法检测ECM组分和细胞信号通路中的关键蛋白（TGF-β 1、Smad 2/3、Cx43、Erk 1/2、MMP-1和胶原III）的表达。伤后颊粘膜创面愈合无瘢痕，皮肤创面愈合有明显瘢痕。然而，TGF-β 1的表达逐渐增加，损伤后第5天; Cx43表达表现出类似的反应，在皮肤中进行性增加，并在第14天达到峰值。相反，口腔粘膜中的TGF-β 1和Cx43表达仍然较低。高水平的TGF-β 1增加p-Smad 2/3水平，然后诱导Cx43，而Cx43的表达增加拮抗Erk 1/2的磷酸化，Erk 1/2是Cx43下游的蛋白质，其影响MMP-1的合成。MMP-1缺乏导致III型胶原积聚并促进瘢痕形成。我们证明了TGF-β 1诱导的Cx43通过Erk/MMP-1/胶原III途径促进瘢痕形成。
Wound healing can be divided into different phases, and timely initiation and cessation of these stages is key to successful wound healing; otherwise, scar tissue forms in the wounded area. Connexins (Cxs) were confirmed to influence scar formation, and Cx43, an indispensable member of the Cx family, was shown to be involved in this process. Our study investigated the regulatory role of Cx43 in scar formation and the possible cell signalling pathways. We established oral mucosa and skin wound healing models in C57BL/6J mice. RT-PCR, western blotting, immunohistochemistry and immunofluorescence were used to examine the expression of ECM components and key proteins in cell signalling pathways (TGF-beta 1, Smad2/3, Cx43, Erk1/2 MMP-1 and collagen III). After injury, buccal mucosa wounds healed with no scar, whereas skin wounds healed with an evident scar. Nevertheless, TGF-beta 1 expression gradually increased by the 5th day after injury; Cx43 expression showed a similar response, with a progressive increase in the skin and a peak on day 14. In contrast, TGF-beta 1 and Cx43 expression in the oral mucosa remained low. The high level of TGF-beta 1 increased p-Smad2/3 levels and then induced Cx43, whereas increased expression of Cx43 antagonised the phosphorylation of Erk1/2, a protein downstream of Cx43, which affected MMP-1 synthesis. MMP-1 deficiency led to collagen III accumulation and facilitated scar formation. We demonstrated that TGF-beta 1-induced Cx43 promotes scar formation via the Erk/MMP-1/collagen III pathway.