title: The Aldo-Keto Reductase AKR1B10 Is Up-Regulated in Keloid Epidermis, Implicating Retinoic Acid Pathway Dysregulation in the Pathogenesis of Keloid Disease.
abstract: Keloid disease is a recurrent fibroproliferative cutaneous tumor of unknown pathogenesis for which clinical management remains unsatisfactory. To obtain new insights into hitherto underappreciated aspects of keloid pathobiology, we took a laser capture microdissection-based, whole-genome microarray analysis approach to identify distinct keloid disease-associated gene expression patterns within defined keloid regions. Identification of the aldo-keto reductase enzyme AKR1B10 as highly up-regulated in keloid epidermis suggested that an imbalance of retinoic acid metabolism is likely associated with keloid disease. Here, we show that AKR1B10 transfection into normal human keratinocytes reproduced the abnormal retinoic acid pathway expression pattern we had identified in keloid epidermis. Cotransfection of AKR1B10 with a luciferase reporter plasmid showed reduced retinoic acid response element activity, supporting the hypothesis of retinoic acid synthesis deficiency in keloid epidermis. Paracrine signals released by AKR1B10-overexpressing keratinocytes into conditioned medium resulted in up-regulation of transforming growth factor-β1, transforming growth factor-β2, and collagens I and III in both keloid and normal skin fibroblasts, mimicking the typical profibrotic keloid profile. Our study results suggest that insufficient retinoic acid synthesis by keloid epidermal keratinocytes may contribute to the pathogenesis of keloid disease. We refocus attention on the role of injured epithelium in keloid disease and identify AKR1B10 as a potential new target in future management of keloid disease.
authors.affiliation: Plastic and Reconstructive Surgery Research, Manchester Institute of Biotechnology, University of Manchester, Manchester, UK.
authors.forename: Natalie
authors.initials: N
authors.lastname: Jumper
authors.affiliation: Plastic and Reconstructive Surgery Research, Manchester Institute of Biotechnology, University of Manchester, Manchester, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Hodgkinson
authors.affiliation: Department of Plastic and Reconstructive Surgery, University of West Indies, Kingston, Jamaica.
authors.forename: Guyan
authors.initials: G
authors.lastname: Arscott
authors.affiliation: Plastic Surgery Unit, Carmel Medical Center, Haifa, Israel.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Har-Shai
authors.affiliation: Centre for Dermatology Research, Institute of Inflammation and Repair, University of Manchester, Manchester, UK; Department of Dermatology, University of Münster, D-48149, Münster, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Paus
authors.affiliation: Plastic and Reconstructive Surgery Research, Manchester Institute of Biotechnology, University of Manchester, Manchester, UK; Centre for Dermatology Research, Institute of Inflammation and Repair, University of Manchester, Manchester, UK. Electronic address: Ardeshir.Bayat@manchester.ac.uk.
authors.forename: Ardeshir
authors.initials: A
authors.lastname: Bayat
mesh_terms: D000449:Aldehyde Reductase / Q000378:metabolism*; D000074408:Aldo-Keto Reductases; D017077:Culture Media, Conditioned; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation; D006801:Humans; D007627:Keloid / Q000378:metabolism* / Q000473:pathology; D015603:Keratinocytes / Q000166:cytology; D020411:Oligonucleotide Array Sequence Analysis; D010957:Plasmids / Q000378:metabolism; D020218:Response Elements; D015398:Signal Transduction; D015533:Transcriptional Activation; D014212:Tretinoin / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D017077:Culture Media, Conditioned; D014212:Tretinoin; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase