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UVB-mediated DNA damage induces matrix metalloproteinases to promote photoaging in an AhR- and SP1-dependent manner
Daniel J. Kim, … , Anna L. Chien, Sewon Kang
Daniel J. Kim, … , Anna L. Chien, Sewon Kang
Published March 22, 2022
Citation Information: JCI Insight. 2022;7(9):e156344. https://doi.org/10.1172/jci.insight.156344.
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Research Article Aging Dermatology

UVB-mediated DNA damage induces matrix metalloproteinases to promote photoaging in an AhR- and SP1-dependent manner

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Abstract

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.

Authors

Daniel J. Kim, Akiko Iwasaki, Anna L. Chien, Sewon Kang

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Figure 5

Treatment with vitamin B12 or FA ameliorates UVB-induced wrinkles and MMP2 expression.

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Treatment with vitamin B12 or FA ameliorates UVB-induced wrinkles and MM...
SKH1 hairless mice were irradiated 3 times a week for 16 weeks with gradually increasing doses. After each irradiation, corn oil, B12, or FA was topically applied to the dorsum of mice. At week 13, mice were evaluated for wrinkle formation. (A) Representative images of wrinkles from the lower dorsum of mice. (B) Wrinkles were graded by blinded investigators using the scale provided by Inomata et al. (11). (C and D) Sections perpendicular to the wrinkles were paraffin-fixed and stained with DAPI and anti-MMP2 antibody with fluorescence IHC. Bands of MMP2 expression for each section were identified at 200× original magnification, and fluorescence was quantified by ImageJ (NIH). (C) Average fluorescence intensity of MMP2 bands by mouse. (D) Representative images of MMP2 bands (white arrows) found on IHC (200× original magnification). Blue indicates DAPI staining; green indicates MMP2 staining. n = 4–5 mice for each treatment group. Data are means ± SEM. P values were calculated by 1-way ANOVA. *P < 0.05, ***P < 0.001, ****P < 0.0001.

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