liu.seSearch for publications in DiVA
Change search
ReferencesLink to record
Permanent link

Direct link
Decreased expression of inhibitory SMAD6 and SMAD7 in keloid scarring
Department of Dermatology, University of Kiel, Kiel, Germany.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
School of Biological Sciences, University of Manchester, Manchester, UK.
School of Biological Sciences, University of Manchester, Manchester, UK.
Show others and affiliations
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.

Place, publisher, year, edition, pages
2006. Vol. 59, no 3, 221-229 p.
Keyword [en]
Keloids; SMAD; TGFβ; TGFβ signalling
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-12814DOI: 10.1016/j.bjps.2005.06.010OAI: diva2:17108
Available from: 2007-12-03 Created: 2007-12-03
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

Open Access in DiVA

No full text

Other links

Publisher's full textLink to Ph.D. thesis

Search in DiVA

By author/editor
Bock (Seifert), Oliver
By organisation
Department of Clinical and Experimental MedicineFaculty of Health Sciences
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 59 hits
ReferencesLink to record
Permanent link

Direct link