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Identification of unique gene expression patterns within different lesional sites of keloids
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
The Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, UK.
Mucosal Immunity, Helmholtz Centre for Infection Research (HCI), Braunschweig, Germany.
Institute of Medical Microbiology, University Hospital Essen, Essen, Germany.
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2008 (English)In: Wound Repair and Regeneration, ISSN 1067-1927 (print) 1524-475X (online), Vol. 16, no 2, 254-265 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2008. Vol. 16, no 2, 254-265 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-12816DOI: 10.1111/j.1524-475X.2007.00343.xOAI: diva2:17110
Available from: 2007-12-03 Created: 2007-12-03 Last updated: 2009-05-14
In thesis
1. Keloids - A fibroproliferative disease
Open this publication in new window or tab >>Keloids - A fibroproliferative disease
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Keloids are a fibroproliferative disorder of unknown etiology developing in the skin after injury or spontaneously. The aim of this thesis is to gain deeper insight into the role of TGF-β and its signaling pathway proteins, SMADs, in the pathogenesis of keloids and describe the gene expression profile in different keloid sites in the search for potential target genes for future treatment. Further aim is to develop an instrument to describe the quality of life of patients with keloids.

We find cultured keloid fibroblasts to express an increased level of TGF-β1 mRNA and a decreased level of TGF-β3 mRNA compared to control skin. Keloid derived fibroblasts exhibit significantly decreased mRNA levels of TGF-β receptor type II (TβRII) and the ratio of TβRI/TβRII mRNA expression is increased. This suggests that a certain expression pattern of TGF-β subtypes and receptors may be important in keloid pathogenesis.

Analysis of keloid derived fibroblasts reveal decreased SMAD3 mRNA expression and decreased ratio of SMAD2/SMAD3 mRNA implicating a disturbed SMAD signaling. Keloid fibroblasts up-regulate SMAD4 protein after stimulation with TGF-β1 and display diminished levels of the inhibitory proteins SMAD6 and 7. This may contribute to unlimited and deregulated TGF-β signaling leading to increased extracellular matrix production (ECM).

The gene expression pattern is described in fibroblasts from different keloid sites using microarrays covering the whole human genome. This study reveals 105 regulated genes (79 genes are up- and 26 down-regulated) resulting in a unique gene expression profile in different sites of keloids, where progression or regression of the keloid process took place. In cells from the central part of keloids with clinical signs of regression, an up-regulation of apoptosis inducing genes as ADAM12 and ECM degrading genes as MMP19 is found. These genes may contribute to regression of keloids and might be possible future target genes for treatment. Overexpression of apoptosis inhibitors as AVEN and down-regulation of angiogenesis inhibiting genes as PTX3 found at the active margin of keloids may be responsible for the invasive character of the keloid margin.

We develop a disease specific questionnaire to measure the quality of life of patients with keloids. We find two scales, psychological and physical impairment, describing the dimensions of quality of life in patients with scars. These two scales are independent of each other and show a high test-retest reliability. Single items which clinically characterize the disease show correlations to these scales. The results of this study demonstrate for the first time a severe impairment of quality of life of patients suffering from keloids and hypertrophic scars.

In conclusion the described alteration in TGF-β expression and its receptors, the disrupted SMAD signaling pathway and the unique gene expression patterns in different keloid sites provide new knowledge on ECM formation and degradation in keloids. Regulatory genes in ECM homeostasis may be future target genes for keloid prevention, regression and treatment. The disease specific quality of life instrument of patients with keloids and scars is a useful tool to estimate success in future therapeutic efforts over time.

Place, publisher, year, edition, pages
Linköping University Electronic Press, 2008. 74 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1023
keloid, TGF-beta, SMAD, quality of life
National Category
Dermatology and Venereal Diseases
urn:nbn:se:liu:diva-10360 (URN)978-91-85895-67-0 (ISBN)
Public defence
2008-01-11, Linden, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Available from: 2007-12-03 Created: 2007-12-03 Last updated: 2015-11-19

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