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

It is currently thought that ultraviolet B (UVB) radiation drives photoaging of the skin primarily by generating reactive oxygen species (ROS). In this model, ROS purportedly activates AP-1 to upregulate matrix metalloproteinases (MMPs) 1, 3, and 9, which then degrade collagen in dermis produce wrinkles. However, these MMPs are expressed at relatively low levels correlate poorly with wrinkles mice, suggesting another mechanism may be more directly associated photoaging. Here we show MMP2, degrades type IV dermal-epidermal junction, abundantly human skin, increases age sun-exposed correlates robustly aryl hydrocarbon receptor (AhR), a transcription factor activated UV-generated photometabolites can suppress repair bulky DNA lesions. Through mechanistic studies HaCaT keratinocytes, found AhR, SP1, other pathways damage required for induction both MMP2 MMP11 (another MMP implicated photoaging) mRNA, but not MMP1/3. Consistent findings, topoisomerase inhibitor was sufficient induce MMP2/11 MMP1/3/9. Lastly, chronic UVB treatment hairless mice generated distinct band-like pattern epidermis while topical AhR antagonists vitamin B12 folic acid ameliorated UVB-induced wrinkle formation dampened expression skin. From data, propose an expanded model whereby UVB-mediated induces through epidermis, ultimately causing focal underlying basement membrane, UV-induced leads degradation I III dermis. This only provides molecular basis complex changes photoaging, also underscores therapeutic potential modulation preventing