UVB-mediated DNA damage induces matrix metalloproteinases to promote photoaging in an AhR- and SP1-dependent manner.
UVB-mediated DNA damage induces matrix metalloproteinases to promote photoaging in an AhR- and SP1-dependent manner.
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DOI：
10.1172/jci.insight.156344
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发表时间：
2022-05-09
期刊：
影响因子：
8
通讯作者：
Kang, Sewon
中科院分区：
文献类型：
--
作者：
Kim, Daniel J.;Iwasaki, Akiko;Chien, Anna L.;Kang, Sewon
目前认为，UVB辐射主要通过产生活性氧来驱动皮肤光老化。在这个模型中，活性氧激活激活蛋白-1，上调MMPs 1、3和9，然后降解胶原蛋白和其他细胞外基质成分，产生皱纹。然而，这些MMPs的表达水平相对较低，与皱纹的相关性较差，这表明另一种不同于ROS和MMP1/3/9的机制可能与光老化更直接相关。本研究表明，降解IV型胶原蛋白的MMP2在人类皮肤中大量表达，在暴露于阳光下的皮肤中随着年龄的增长而增加，并与芳烃受体（AhR）密切相关，AhR是一种由紫外线产生的光代谢产物直接激活的转录因子。通过HaCaT人类永生化角质形成细胞的机制研究，我们发现AhR、特异性蛋白1 （SP1）和其他与DNA损伤相关的途径是诱导MMP2和MMP11（另一种与光老化有关的MMP）所必需的，但不是MMP1/3。最后，我们发现用AhR拮抗剂维生素B12和叶酸局部治疗可以改善uvb诱导的小鼠皱纹形成，同时抑制皮肤中MMP2的表达。这些结果直接暗示了光老化中的DNA损伤，并揭示了AhR是预防皱纹的潜在目标。
It is currently thought that UVB radiation drives photoaging of the skin primarily by generating ROS. In this model, ROS purportedly activates activator protein-1 to upregulate MMPs 1, 3, and 9, which then degrade collagen and other extracellular matrix components to produce wrinkles. However, these MMPs are expressed at relatively low levels and correlate poorly with wrinkles, suggesting that another mechanism distinct from ROS and MMP1/3/9 may be more directly associated with photoaging. Here we show that MMP2, which degrades type IV collagen, is abundantly expressed in human skin, increases with age in sun-exposed skin, and correlates robustly with aryl hydrocarbon receptor (AhR), a transcription factor directly activated by UV-generated photometabolites. Through mechanistic studies with HaCaT human immortalized keratinocytes, we found that AhR, specificity protein 1 (SP1), and other pathways associated with DNA damage are required for the induction of both MMP2 and MMP11 (another MMP implicated in photoaging), but not MMP1/3. Last, we found that topical treatment with AhR antagonists vitamin B12 and folic acid ameliorated UVB-induced wrinkle formation in mice while dampening MMP2 expression in the skin. These results directly implicate DNA damage in photoaging and reveal AhR as a potential target for preventing wrinkles.
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影响因子：
3.8
作者：
Oh KS;Bustin M;Mazur SJ;Appella E;Kraemer KH
通讯作者：
Kraemer KH
影响因子：
14.2
作者：
HOFFMAN, DR;WOOD, CL;HUDSON, P
通讯作者：
HUDSON, P
DOI：
10.1016/j.jphotobiol.2013.03.001
发表时间：
2013-05-05
影响因子：
5.4
作者：
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通讯作者：
Nizauskaite, Zivile
影响因子：
5.5
作者：
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通讯作者：
Haas, Tara L.
DOI：
10.1073/pnas.0701764104
发表时间：
2007-05-22
影响因子：
11.1
作者：
Fritsche, Ellen;Schaefer, Claudia;Krutmann, Jean
通讯作者：
Krutmann, Jean