Keloid disease is a significant clinical problem, especially in black populations, with an estimated incidence of 4-16%. Keloids are fibroproliferative dermal tumors developing as a result of deregulated wound healing. The dynamic nature of keloids is illustrated by clinical regression in the center, while the margin remains active growing into the surrounding healthy skin. Therefore, the gene expression profiles of fibroblasts from different sites of the keloids were characterized using Affymetrix microarrays covering the whole human genome. This study revealed 105 genes that were differentially regulated (79 genes were up-regulated and 26 down-regulated) in a unique gene expression profile in different sites of keloids where progression or regression of the process was in progress. The apoptosis inhibitor AVEN was found to be up-regulated at the active margin of keloids, while apoptosis-inducing genes such as ADAM12 and genes inducing extracellular matrix (ECM) degradation such as matrix metalloproteinase-19 were up-regulated in the regressing keloid center. We identified genes previously not described in the development of keloids. Activating proapoptotic genes or inhibiting ECM-inducing genes as INHBA or monocyte chemoattractant protein-1 might be possible target genes for new treatment strategies for keloid disease.
Keloid scars are common benign fibroproliferative reticular dermal lesions with unknown etiology and ill-defined management with high rate of recurrence post surgery. The progression of keloids is characterized by increased deposition of extracellular matrix proteins, invasion into the surrounding healthy skin and inflammation. Fibroblasts are considered to be the key cellular mediators of fibrogenesis in keloid scars. Fibroblast activation protein alpha (FAP-α) and dipeptidyl peptidase IV (DPPIV) are proteases located at the plasma membrane promoting cell invasiveness and tumor growth and have been previously associated with keloid scars. Therefore, in this study we analyzed in further detail the expression of FAP-α in keloid fibroblasts compared to control skin fibroblasts. Dermal fibroblasts were obtained from punch-biopsies from the active margin of four keloids and four control skin samples. Flow cytometry was used to analyze FAP-α expression and the CytoSelect 24-Well Collagen I Cell Invasion Assay was applied to study fibroblast invasion. Secretion of extracellular matrix (ECM) proteins was investigated by multiplexed particle-based flow cytometric assay and enzyme-linked immunosorbent assay. We found an increased expression of FAP-α in keloid fibroblasts compared to control skin fibroblasts (p < 0.001). Inhibition of FAP-α/DPPIV activity using the irreversible inhibitor H(2)N-Gly-Pro diphenylphosphonate reduced the increased invasiveness of keloid fibroblasts (p < 0.001) indicating that keloid invasion may be partly FAP-α/DPPIV mediated. FAP-α/DPPIV inhibition had no effect, (a) on the synthesis of the ECM proteins procollagen type I C-terminal peptide and fibronectin, (b) on the production of fibroblast growth factor or vascular endothelial growth factor, (c) on the expression of the proinflammatory cytokines interleukin-6 (IL-6), interleukin 8 (IL-8) or monocyte chemotactic protein-1. These results suggest a potential role for FAP-α and DPPIV in the invasive behavior of keloids. FAP-α and DPPIV may increase the invasive capacity of keloid fibroblasts rather than by modulating inflammation or ECM production. Since FAP-α expression is restricted to reactive fibroblasts in wound healing and normal adult tissues are generally FAP-α negative, inhibiting FAP-α/DPPIV activity may be a novel treatment option to prevent keloid progression.
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