Abstract
BackgroundCathepsin K (CatK), a cysteine protease with the potent elastolytic activity, plays a predominant role in intracellular elastin degradation in human dermal fibroblasts (HDFs), and contributes to solar elastosis. In previous studies, CatK expression was downregulated in photoaged skin and fibroblasts, but upregulated in acute UVA-irradiated skin and fibroblasts. The underlying mechanisms regulating UVA-induced CatK expression remain elusive.ObjectiveThis study investigates mechanisms involved in the regulation of UVA-induced CatK expression in HDFs.MethodsPrimary HDFs were exposed to UVA. Cell proliferation was analyzed using a colorimetric assay of relative cell number. Quantitative real-time RT-PCR and Western blot were performed to detect CatK expression in HDFs on three consecutive days after 10 J/cm2 UVA irradiation, or cells treated with increasing UVA doses. UVA-activated MAPK/AP-1 pathway was examined by Western blot. Effects of inhibition of MAPK pathway and knockdown of Jun and Fos on UVA-induced CatK expression were also measured by real-time RT-PCR and Western blot.ResultsUVA significantly increased CatK mRNA and protein expression in a dose-dependent manner. UVA-induced CatK expression occurred along with UVA-activated phosphorylation of JNK, p38 and Jun, UVA-increased expression of Fos. Inactivation of JNK and p38MAPK pathways both remarkably decreased UVA-induced CatK expression, which was suppressed more by inhibition of JNK pathway. Furthermore, knockdown of Jun and Fos significantly attenuated basal and UVA-induced CatK expression.ConclusionUVA is capable of increasing CatK expression in HDFs, most likely by activation of MAPK pathway and of AP-1, which has been shown to be the case for matrix metalloproteinases. As current strategies for selecting anti-photoaging agents focus on their ability to decrease MMPs' expression through inhibiting UV- activated MAPK pathway, future strategies should also consider their effect on CatK expression.
Highlights
Photoaging is histologically characterized by reduced content of dermal collagen fibers and accumulation of dystrophic elastotic material, the latter commonly termed solar elastosis [1]
UVA is capable of increasing Cathepsin K (CatK) expression in human dermal fibroblasts (HDFs), most likely by activation of mitogen-activated protein kinase (MAPK) pathway and of AP-1, which has been shown to be the case for matrix metalloproteinases
As current strategies for selecting anti-photoaging agents focus on their ability to decrease matrix metalloproteinases (MMPs)’ expression through inhibiting UV- activated MAPK pathway, future strategies should consider their effect on CatK expression
Summary
Photoaging is histologically characterized by reduced content of dermal collagen fibers and accumulation of dystrophic elastotic material, the latter commonly termed solar elastosis [1]. The pathogenesis of solar elastosis has been considered mainly because of overproduction and/or decreased degradation of elastic fibers [2], the exact mechanism remains elusive. MMP-2, MMP-7, MMP-9 and MMP-12 have elastolytic activity [4,5] All these proteases are secreted to mediate elastin degradation in the extracellular space. Sustained increase of their expression has been shown in the UV-exposed skin [4,6], yet they can’t counteract the increased synthesis of elastin in solar elastosis. Cathepsin K (CatK), a cysteine protease with the potent elastolytic activity, plays a predominant role in intracellular elastin degradation in human dermal fibroblasts (HDFs), and contributes to solar elastosis. The underlying mechanisms regulating UVA-induced CatK expression remain elusive
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