Abstract
Epidermolysis bullosa refers to a group of genodermatoses that affects the integrity of epithelial layers, phenotypically resulting in severe skin blistering. Dowling-Meara, the major subtype of epidermolysis bullosa simplex, is inherited in an autosomal dominant manner and can be caused by mutations in either the keratin-5 (K5) or the keratin-14 (K14) gene. Currently, no therapeutic approach is known, and the main objective of this study was to identify novel therapeutic targets. We used microarray analysis, semi-quantitative real-time PCR, western blot and ELISA to identify differentially regulated genes in two K14 mutant cell lines carrying the mutations K14 R125P and K14 R125H, respectively. We found kallikrein-related peptidases and matrix metalloproteinases to be upregulated. We also found elevated expression of chemokines, and we observed deregulation of the Cdc42 pathway as well as aberrant expression of cytokeratins and junction proteins. We further demonstrated, that expression of these genes is dependent on interleukin-1 β signaling. To evaluate these data in vivo we analysed the blister fluids of epidermolysis bullosa simplex patients vs. healthy controls and identified matrix metalloproteinase-9 and the chemokine CXCL8/IL-8 as potential therapeutic targets.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adolescent
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Adult
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Aged
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Antibodies, Monoclonal / pharmacology
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Cell Line, Transformed
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Child
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Child, Preschool
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Connexins / genetics
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Connexins / metabolism
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Cytoskeletal Proteins / metabolism
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Epidermolysis Bullosa Simplex / drug therapy
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Epidermolysis Bullosa Simplex / genetics
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Epidermolysis Bullosa Simplex / metabolism*
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Gene Expression Profiling
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Gene Expression Regulation / drug effects
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Humans
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Infant
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Interleukin-1beta / antagonists & inhibitors
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Interleukin-8 / genetics
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Interleukin-8 / metabolism*
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Kallikreins / genetics
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Kallikreins / metabolism
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Keratins / genetics
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Keratins / metabolism
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Matrix Metalloproteinase 9 / genetics
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Matrix Metalloproteinase 9 / metabolism*
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Membrane Proteins / metabolism
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Middle Aged
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Mutation
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Phosphorylation
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Rho Guanine Nucleotide Exchange Factors / genetics
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Rho Guanine Nucleotide Exchange Factors / metabolism
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Young Adult
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cdc42 GTP-Binding Protein / metabolism
Substances
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ARHGEF9 protein, human
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Antibodies, Monoclonal
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Connexins
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Cytoskeletal Proteins
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Interleukin-1beta
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Interleukin-8
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Membrane Proteins
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Rho Guanine Nucleotide Exchange Factors
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ezrin
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radixin
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Keratins
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Kallikreins
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Matrix Metalloproteinase 9
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cdc42 GTP-Binding Protein
Grants and funding
This work was supported by DEBRA Austria. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.