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Keloids - A fibroproliferative disease
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
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.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1023
Keyword [en]
keloid, TGF-beta, SMAD, quality of life
National Category
Dermatology and Venereal Diseases
Identifiers
URN: urn:nbn:se:liu:diva-10360ISBN: 978-91-85895-67-0 (print)OAI: oai:DiVA.org:liu-10360DiVA: diva2:17111
Public defence
2008-01-11, Linden, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2007-12-03 Created: 2007-12-03 Last updated: 2015-11-19
List of papers
1. Studies of Transforming Growth Factors Beta 1–3 and their Receptors I and II in Fibroblast of Keloids and Hypertrophic Scars
Open this publication in new window or tab >>Studies of Transforming Growth Factors Beta 1–3 and their Receptors I and II in Fibroblast of Keloids and Hypertrophic Scars
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2005 (English)In: Acta Dermato-Venereologica, ISSN 0001-5555, Vol. 85, no 3, 216-220 p.Article in journal (Refereed) Published
Abstract [en]

Keloids are benign skin tumours occurring during wound healing in genetically predisposed patients. They are characterized by an abnormal deposition of extracellular matrix components, particularly collagen. There is uncertain evidence that transforming growth factor-beta (TGFβ) is involved in keloid formation. Therefore we investigated the expression of TGFβ1, 2 and 3 and their receptors in keloids, hypertrophic scars and normal skin. Dermal fibroblasts were obtained from punch biopsies of patients with keloids and hypertrophic scars and from normal skin of healthy individuals. Total RNA was isolated and the expression of TGFβ1, 2 and 3 and of TGFβ receptors I and II (TGFβRI and II) was analysed by real-time PCR using the Lightcycler technique. Our data demonstrate significantly lower TGFβ2 mRNA expression in hypertrophic scar fibroblasts as compared with fibroblasts derived from keloids and normal skin (p<0.05). In contrast, TGFβ3 mRNA expression was significantly lower in keloid fibroblasts in comparison with fibroblasts derived from hypertrophic scar and normal skin (p<0.01). TGFβRI mRNA expression was significantly decreased in hypertrophic scar fibroblasts (p<0.01) and TGFβRII mRNA expression was decreased in keloids compared with hypertrophic scar fibroblasts (p<0.001), The ratio of TGFβRI/TGFβRII expression was increased in keloids compared with hypertrophic scar and normal skin fibroblasts. As recently supposed, an increased TGFβRI/TGFβRII ratio could promote fibrosis. Therefore our data support a possible role of TGFβRI and TGFβRII in combination with a certain TGFβ expression pattern as fibrosis-inducing factors in keloids.

Keyword
wound healing, fibroblasts, TGFβ receptors
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-12813 (URN)10.1080/00015550410025453 (DOI)
Available from: 2007-12-03 Created: 2007-12-03 Last updated: 2011-01-11
2. Decreased expression of inhibitory SMAD6 and SMAD7 in keloid scarring
Open this publication in new window or tab >>Decreased expression of inhibitory SMAD6 and SMAD7 in keloid scarring
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2006 (English)In: Journal of Plastic, Reconstructive and Aesthetic Surgery, ISSN 1748-6815, Vol. 59, no 3, 221-229 p.Article in journal (Refereed) Published
Abstract [en]

Keloids are benign skin tumours occurring during wound healing in genetically predisposed patients. They are characterised by an abnormal deposition of extracellular matrix components, in particular collagen. There is evidence that transforming growth factor-beta (TGFβ) is involved in keloid formation. SMAD proteins play a crucial role in TGFβ signaling and in terminating the TGFβ signal by a negative feedback loop through SMAD6 and 7. It is unclear how TGFβ signalling is connected to the pathogenesis of keloids. Therefore, we investigated the expression of SMAD mRNA and proteins in keloids, in normal skin and in normal scars.

Dermal fibroblasts were obtained from punch-biopsies of keloids, normal scars and normal skin. Cells were stimulated with TGFβ1 and the expression of SMAD2, 3, 4, 6 and 7 mRNA was analysed by real time RT-PCR. Protein expression was determined by Western blot analysis.

Our data demonstrate a decreased mRNA expression of the inhibitory SMAD6 and 7 in keloid fibroblasts as compared to normal scar (p<0.01) and normal skin fibroblasts (p<0.05). SMAD3 mRNA was found to be lower in keloids (p<0.01) and in normal scar fibroblasts (p<0.001) compared to normal skin fibroblasts.

Our data showed for the first time a decreased expression of the inhibitory SMAD6 and SMAD7 in keloid fibroblasts. This could explain why TGFβ signaling is not terminated in keloids leading to overexpression of extracellularmatrix in keloids. These data support a possible role of SMAD6 and 7 in the pathogenesis of keloids.

Keyword
Keloids; SMAD; TGFβ; TGFβ signalling
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-12814 (URN)10.1016/j.bjps.2005.06.010 (DOI)
Available from: 2007-12-03 Created: 2007-12-03
3. Quality of life of patients with keloid and hypertrophic scarring
Open this publication in new window or tab >>Quality of life of patients with keloid and hypertrophic scarring
2006 (English)In: Archives of dermatological research, ISSN 0340-3696, Vol. 297, no 10, 433-438 p.Article in journal (Refereed) Published
Abstract [en]

Keloid and hypertrophic scarring represent chronic disfiguring dermatoses with a high resistance to therapy. The aim of our study was to assess for the first time the quality of life of patients with hypertrophic scars and keloids, because they suffer from quality of life impairment as much as patients with other chronic skin diseases. An item-pool was created modifying and supplementing the items of the Questionnaire on Experience with Skin Complaints. This questionnaire was distributed to 100 outpatients with keloids and hypertrophic scars. A factor analysis was used to identify the underlying dimensions. Two scales (psychological and physical impairment) of the questionnaire with nine and five items, respectively, were established. Test–retest reliability of the questionnaire was excellent (corr>0.9). Good validity was suggested by the correlation of physical impairment with pain (P≤0.001), pruritus (P<0.001), and the amount of restriction of mobility (P<0.001). The psychological scale was associated with pain and restriction of mobility, although the correlations were lower. This study demonstrates for the first time an impairment of quality of life in a large group of patients with keloid and hypertrophic scarring.

Keyword
Quality of life, Keloid, Hypertrophic scarring
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-12815 (URN)10.1007/s00403-006-0651-7 (DOI)
Available from: 2007-12-03 Created: 2007-12-03 Last updated: 2010-05-19
4. Identification of unique gene expression patterns within different lesional sites of keloids
Open this publication in new window or tab >>Identification of unique gene expression patterns within different lesional sites of keloids
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2008 (English)In: Wound Repair and Regeneration, ISSN 1067-1927, 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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-12816 (URN)10.1111/j.1524-475X.2007.00343.x (DOI)
Available from: 2007-12-03 Created: 2007-12-03 Last updated: 2009-05-14

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