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  • 1.
    Assarsson, Malin
    et al.
    Div Dermatol and Venereol, Sweden.
    Duvetorp, Albert
    Div Dermatol and Venereol, Sweden.
    Dienus, Olaf
    Div Med Diagnost, Sweden.
    Söderman, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Div Med Diagnost, Sweden.
    Seifert, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Div Dermatol and Venereol, Sweden.
    Significant Changes in the Skin Microbiome in Patients with Chronic Plaque Psoriasis after Treatment with Narrowband Ultraviolet B2018In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 98, no 4, p. 428-436Article in journal (Refereed)
    Abstract [en]

    Changes in the skin microbiome have been shown to promote cutaneous inflammation. The skin microbiome of patients with chronic plaque type psoriasis was analysed before and after treatment with narrowband ultraviolet B (UVB). Swab samples of the microbiome were taken from lesional and non-lesional skin of 26 patients. Microbiotas were characterized by sequencing 16S rRNA bacterial genes on the Illumina MiSeq platform. Lesional skin microbiome diversity correlated with psoriasis severity (measured with the Psoriasis Area and Severity Index; PASI). There was a significantly lower abundance of the phylum Firmicutes and the genus Staphylococcus in lesional skin compared with non-lesional skin before UVB treatment. Responders (amp;gt; 75% target Psoriasis Severity Index (PSI) improvement) had significantly lower abundance of the phyla Firmicutes in lesional and non-lesional skin and lower abundance of the genera Staphylococcus, Finegoldia, Anaerococcus, Peptoniphilus, Gardnerella, Prevotella and Clostridium in lesional skin after UVB treatment. Pseudomonas significantly decreased in lesional and non-lesional skin of treatment responders. These results suggest that skin microbiome alterations after UVB treatment could be related to treatment and treatment response.

  • 2.
    Assarsson, Malin
    et al.
    Ryhov Hosp, Sweden.
    Soderman, Jan
    Ryhov Hosp, Sweden.
    Duvetorp, Albert
    Skanes Univ Hosp, Sweden.
    Mrowietz, Ulrich
    Univ Med Ctr Schleswig Holstein, Germany.
    Skarstedt, Marita
    Ryhov Hosp, Sweden.
    Seifert, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Ryhov Hosp, Sweden.
    Narrowband UVB treatment induces expression of WNT7B, WNT10B and TCF7L2 in psoriasis skin2019In: Archives of Dermatological Research, ISSN 0340-3696, E-ISSN 1432-069X, Vol. 311, no 7, p. 535-544Article in journal (Refereed)
    Abstract [en]

    WNT/beta-catenin signaling pathways play a pivotal role in the human immune defense against infections and in chronic inflammatory conditions as psoriasis. Wnt gene alterations are linked to known comorbidities of psoriasis as obesity, diabetes and Crohns disease. The objective of this study was to investigate WNT7B, WNT10B, WNT16 and TCF7L2 gene and protein expression in lesional and non-lesional skin and in the peripheral blood of patients with chronic plaque psoriasis compared with healthy individuals. To investigate the effect of narrowband UVB radiation, expression of these genes were analyzed before and after narrowband UVB treatment. Associations between single nucleotide polymorphisms for WNT7B, WNT10B, WNT16 and TCF7L2 genes and psoriasis were tested. Our results show significantly decreased WNT7B, WNT10B and TCF7L2 gene expression in lesional skin compared with non-lesional skin and healthy controls. Narrowband UVB treatment significantly increased expression of these genes in lesional skin. Immunohistochemistry shows increased WNT16 expression in lesional skin. No significant differences in allele or genotype frequencies for Wnt or TCF7L2 gene polymorphisms were found between patient and control group. This study shows for the first time significant UVB induced upregulation of WNT7B, WNT10B and TCF7L2 in patients with psoriasis and suggests a potential role of these genes in psoriasis pathogenesis.

  • 3.
    Bock (Seifert), Oliver
    et al.
    Primary Health Care Center, Jönköping.
    Schmid-Ott, Gerhard
    Department of Psychosomatic and Psychotherapy, Hannover Medical School, Hannover, Germany.
    Malewski, Peter
    Department of Psychosomatic and Psychotherapy, Hannover Medical School, Hannover, Germany.
    Mrowietz, Ulrich
    Department of Dermatology, University of Kiel, Kiel, Germany.
    Quality of life of patients with keloid and hypertrophic scarring2006In: Archives of dermatological research, ISSN 0340-3696, Vol. 297, no 10, p. 433-438Article in journal (Refereed)
    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.

  • 4.
    Bock (Seifert), Oliver
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Yu, Haiyan
    Department of Dermatology, Sir Run Run Shaw Hospital, Medical College, Zhejiang University,.
    Zitron, Swantje
    Department of Dermatology, University of Kiel, Kiel, Germany.
    Bayat, Ardeshir
    School of Biological Sciences, University of Manchester, Manchester, UK.
    Ferguson, Mark WJ
    School of Biological Sciences, University of Manchester, Manchester, UK.
    Mrowietz, Ulrich
    Department of Dermatology, University of Kiel, Kiel, Germany.
    Studies of Transforming Growth Factors Beta 1–3 and their Receptors I and II in Fibroblast of Keloids and Hypertrophic Scars2005In: Acta Dermato-Venereologica, ISSN 0001-5555, Vol. 85, no 3, p. 216-220Article in journal (Refereed)
    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.

  • 5.
    Danielsen, Kjersti
    et al.
    UiT, Norway; Univ Hosp North Norway, Norway.
    Duvetorp, Albert
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Skanes Univ Sjukhus, Sweden.
    Iversen, Lars
    Aarhus Univ Hosp, Denmark.
    Ostergaard, Mikkel
    Univ Copenhagen, Denmark.
    Seifert, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Ryhov Hosp, Sweden.
    Steinar Tveit, Kare
    Haukeland Hosp, Norway.
    Skov, Lone
    Univ Copenhagen, Denmark.
    Prevalence of Psoriasis and Psoriatic Arthritis and Patient Perceptions of Severity in Sweden, Norway and Denmark: Results from the Nordic Patient Survey of Psoriasis and Psoriatic Arthritis2019In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 99, no 1, p. 18-25Article in journal (Refereed)
    Abstract [en]

    Optimal clinical management of psoriasis and psoriatic arthritis (PsA) requires understanding of the impact on patients. The NORdic PAtient survey of Psoriasis and PsA (NORPAPP) aimed to obtain current data on disease prevalence and patient perceptions in Sweden, Denmark and Norway. Among 22,050 individuals questioned, the reported prevalence of psoriasis and/or PsA was 9.7% (5.7% physician-diagnosed plus 4.0% self-diagnosed only); prevalence was similar in Sweden (9.4%) and Denmark (9.2%) but significantly higher in Norway (11.9%). Of those reporting a physicians diagnosis, 74.6% reported psoriasis alone, 10.3% PsA alone and 15.1% both. Patients with PsA perceived their disease to be more severe than those with psoriasis; patients with PsA and psoriasis reported greater disease severity than those with each condition alone. Patients perceptions of psoriasis severity correlated weakly (Spearmans rho 0.42) with clinical severity; both patient perceptions and clinical measures are important in the assessment and management of psoriasis.

  • 6.
    Duvetorp, Albert
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Skanes Univ Sjukhus, Sweden.
    Ostergaard, M.
    Univ Copenhagen, Denmark.
    Skov, L.
    Univ Copenhagen, Denmark.
    Seifert, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Ryhov Hosp, Sweden.
    Tveit, K. S.
    Haukeland Hosp, Norway.
    Danielsen, K.
    UiT Arctic Univ Norway, Norway; Univ Hosp North Norway, Norway.
    Iversen, Lars
    Aarhus Univ Hosp, Denmark.
    Quality of life and contact with healthcare systems among patients with psoriasis and psoriatic arthritis: results from the NORdic PAtient survey of Psoriasis and Psoriatic arthritis (NORPAPP)2019In: Archives of Dermatological Research, ISSN 0340-3696, E-ISSN 1432-069X, Vol. 311, no 5, p. 351-360Article in journal (Refereed)
    Abstract [en]

    Psoriasis (skin psoriasis, PsO) is a chronic inflammatory condition. In about one-third of cases, the joints are affected (psoriatic arthritis, PsA). Both conditions, especially PsA, profoundly impact patients health-related quality of life (HRQoL). To describe the impact of psoriasis on HRQoL and patients contact with the healthcare system in Sweden, Denmark, and Norway, the NORdic PAtient survey of Psoriasis and Psoriatic arthritis (NORPAPP) asked 22,050 adults randomly selected in Sweden, Denmark and Norway if they had psoriasis. 1264 individuals who reported physician-diagnosed PsO/PsA were invited to the full survey; 1221 responded (74.6% diagnosed with PsO alone; 25.4% with PsA +/- PsO). Respondents with PsA most frequently consulted a rheumatologist; however, 14.3% had never seen a rheumatologist. Respondents with PsO alone most frequently consulted a general practitioner and 10.7% had never seen a dermatologist (although those with severe symptoms visited dermatologists more often). Negative impacts on HRQoL were reported by 38.1% of respondents with PsO [mostly limitations on clothing (22.6%), sleep disorders (16%), and depression/anxiety (16%)] and by 73% of respondents with PsA [mostly limitations on clothing (41.8%), sports/leisure (44.0%), or daily routine (45.1%) and sleeping disorders]. Absence from work/education was more common with PsA +/- PsO (51.9%) than PsO alone (15.1%). In this survey in Sweden, Denmark, and Norway, the impact of psoriasis on the respondents HRQoL was profound and was greater for PsA than for PsO, as was sickness absence. Sleeping disorders and depression were common and should not be overlooked.

  • 7.
    Duvetorp, Albert
    et al.
    Regional Jönköping County, Sweden.
    Slind Olsen, Renate
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Regional Jonköping County, Sweden.
    Nyström, Helena
    Regional Jonköping County, Sweden.
    Skarstedt, Marita
    Regional Jonköping County, Sweden.
    Dienus, Olaf
    Regional Jonköping County, Sweden.
    Mrowietz, Ulrich
    University of Medical Centre Schleswig Holstein, Germany.
    Soederman, Jan
    Regional Jonköping County, Sweden.
    Seifert, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Regional Jonköping County, Sweden.
    Expression of low-density lipoprotein-related receptors 5 and 6 (LRP5/6) in psoriasis skin2017In: Experimental dermatology, ISSN 0906-6705, E-ISSN 1600-0625, Vol. 26, no 11, p. 1033-1038Article in journal (Refereed)
    Abstract [en]

    Low-density lipoprotein-related receptors 5 and 6 (LRP5/6) are transmembrane receptors with key functions in canonical Wnt signalling. Wnt ligands are thought to play an important role in innate immunity and psoriasis, and recent studies assigned LRP5/6 anti-inflammatory properties. The objective of this study was to investigate the expression of LRP5 and LRP6 in lesional and non-lesional skin in peripheral blood and in mononuclear cells of patients with chronic plaque type psoriasis compared with control individuals. To investigate the effect of UV-B radiation, LRP5/6 skin gene expression was analysed before and after narrowband UV-B treatment. Our results showed significantly decreased gene expression of LRP5 and LRP6 in lesional skin and in peripheral blood from patients with psoriasis compared with non-lesional skin and healthy control skin. Immunohistochemistry did not reveal differences in protein expression of LRP5/6. Narrowband UV-B treatment induced a significant increase in LRP5 and LRP6 gene expression in lesional skin. Decreased gene expression of LRP5/6 in lesional skin and upregulation after nb UV-B treatment suggest a possible role for LRP5/6 in psoriasis.

  • 8.
    Duvetorp, Albert
    et al.
    Regional Jönköping County, Sweden.
    Slind Olsen, Renate
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Regional Jonköping County, Sweden.
    Skarstedt, Marita
    Regional Jonköping County, Sweden.
    Söderman, Jan
    Regional Jonköping County, Sweden.
    Seifert, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Regional Jonköping County, Sweden.
    Psoriasis and Pro-angiogenetic Factor CD93: Gene Expression and Association with Gene Polymorphism Suggests a Role in Disease Pathogenesis2017In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 97, no 8, p. 916-921Article in journal (Refereed)
    Abstract [en]

    CD93 is involved in angiogenesis and inflammation, both of which are key processes in the pathogenesis of psoriasis. CD93 was studied in serum, peripheral blood mononuclear cells and skin of patients with psoriasis and controls. Furthermore, allele frequencies for CD93 single-nucleotide polymorphisms rs2749812 and rs2749817 were assessed in patients with psoriasis compared with controls and the effect of narrow-band ultraviolet B (NB-UVB) treatment on CD93 gene expression was evaluated in the skin of patients with psoriasis. CD93 gene expression was significantly increased in lesional and non-lesional skin from patients with psoriasis compared with controls. Immunohistochemistry revealed CD93 staining in dermal endothelial cells in lesional skin, and psoriasis was significantly associated with rs2749817 CD93 gene polymorphism. NB-UVB treatment of patients with psoriasis did not alter skin CD93 gene expression. Increased protein expression of CD93 psoriatic skin and association with the rs2749817 polymorphism suggests that CD93 plays a role in psoriasis disease pathogenesis.

  • 9.
    Duvetorp, Albert
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Skane Univ Hosp, Sweden.
    Söderman, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Ryhov Cty Hosp, Sweden.
    Assarsson, Malin
    Ryhov Cty Hosp, Sweden.
    Skarstedt, Marita
    Ryhov Cty Hosp, Sweden.
    Svensson, Ake
    Skane Univ Hosp, Sweden.
    Seifert, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Ryhov Cty Hosp, Sweden.
    Observational study on Swedish plaque psoriasis patients receiving narrowband-UVB treatment show decreased S100A8/A9 protein and gene expression levels in lesional psoriasis skin but no effect on S100A8/A9 protein levels in serum2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 3, article id e0213344Article in journal (Refereed)
    Abstract [en]

    S100A8 and S100A9 proteins are highly upregulated in patients with psoriasis and have been proposed as potential biomarkers for psoriasis. The present study was designed to analyze the effect of narrowband ultraviolet B therapy on these proteins. S100A8, S100A9 gene expression and S100A8/A9 heterocomplex protein levels were analyzed in lesional and non-lesional skin before and after narrowband-UVB treatment in patients with chronic plaque type psoriasis. In addition, disease severity was measured by psoriasis area and severity index (PASI) and serum protein levels of S100A8/A9 were repeatedly analyzed. Narrowband-UVB treatment significantly reduced S100A8, S100A9 gene expression and S100A8/A9 protein levels in lesional skin while serum levels showed no significant change. No correlation between PASI and serum S100A8/A9 protein levels was found. These results implicate a role of S100A8/A9 in the anti-inflammatory effect of narrowband-UVB. Serum S100A8/A9 levels do not respond to treatment suggesting that serum S100A8/A9 does not originate from psoriasis skin keratinocytes. Serum S100A8/A9 levels do not correlate with PASI questioning serum S100A8/A9 as a biomarker for psoriasis skin activity.

  • 10.
    Gawel, Danuta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Serra-Musach, Jordi
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Lilja, Sandra
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Aagesen, Jesper
    Reg Jonkoping Cty, Sweden.
    Arenas, Alex
    Univ Rovira and Virgili, Spain.
    Asking, Bengt
    Reg Jonkoping Cty, Sweden.
    Bengner, Malin
    Reg Jonkoping Cty, Sweden.
    Bjorkander, Janne
    Reg Jonkoping Cty, Sweden.
    Biggs, Sophie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Hjortswang, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Karlsson, Jan-Erik
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Reg Jonkoping Cty, Sweden.
    Köpsén, Mattias
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Jung Lee, Eun Jung
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Yonsei Univ, South Korea.
    Lentini, Antonio
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Li, Xinxiu
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Magnusson, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Martinez, David
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Matussek, Andreas
    Reg Jonkoping Cty, Sweden; Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Nestor, Colm
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Schafer, Samuel
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Seifert, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Reg Jonkoping Cty, Sweden.
    Sonmez, Ceylan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Stjernman, Henrik
    Reg Jonkoping Cty, Sweden.
    Tjärnberg, Andreas
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Wu, Simon
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Åkesson, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Reg Jonkoping Cty, Sweden.
    Shalek, Alex K.
    MIT, MA 02139 USA; Broad Inst MIT and Harvard, MA 02142 USA; Ragon Inst MGH MIT and Harvard, MA USA.
    Stenmarker, Margaretha
    Reg Jonkoping Cty, Sweden; Inst Clin Sci, Sweden.
    Zhang, Huan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Gustafsson, Mika
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Benson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus Linköping/Motala.
    A validated single-cell-based strategy to identify diagnostic and therapeutic targets in complex diseases2019In: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 11, article id 47Article in journal (Refereed)
    Abstract [en]

    Background

    Genomic medicine has paved the way for identifying biomarkers and therapeutically actionable targets for complex diseases, but is complicated by the involvement of thousands of variably expressed genes across multiple cell types. Single-cell RNA-sequencing study (scRNA-seq) allows the characterization of such complex changes in whole organs.

    Methods

    The study is based on applying network tools to organize and analyze scRNA-seq data from a mouse model of arthritis and human rheumatoid arthritis, in order to find diagnostic biomarkers and therapeutic targets. Diagnostic validation studies were performed using expression profiling data and potential protein biomarkers from prospective clinical studies of 13 diseases. A candidate drug was examined by a treatment study of a mouse model of arthritis, using phenotypic, immunohistochemical, and cellular analyses as read-outs.

    Results

    We performed the first systematic analysis of pathways, potential biomarkers, and drug targets in scRNA-seq data from a complex disease, starting with inflamed joints and lymph nodes from a mouse model of arthritis. We found the involvement of hundreds of pathways, biomarkers, and drug targets that differed greatly between cell types. Analyses of scRNA-seq and GWAS data from human rheumatoid arthritis (RA) supported a similar dispersion of pathogenic mechanisms in different cell types. Thus, systems-level approaches to prioritize biomarkers and drugs are needed. Here, we present a prioritization strategy that is based on constructing network models of disease-associated cell types and interactions using scRNA-seq data from our mouse model of arthritis, as well as human RA, which we term multicellular disease models (MCDMs). We find that the network centrality of MCDM cell types correlates with the enrichment of genes harboring genetic variants associated with RA and thus could potentially be used to prioritize cell types and genes for diagnostics and therapeutics. We validated this hypothesis in a large-scale study of patients with 13 different autoimmune, allergic, infectious, malignant, endocrine, metabolic, and cardiovascular diseases, as well as a therapeutic study of the mouse arthritis model.

    Conclusions

    Overall, our results support that our strategy has the potential to help prioritize diagnostic and therapeutic targets in human disease.

  • 11.
    Seifert (Bock), Oliver
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Keloids - A fibroproliferative disease2008Doctoral 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.

    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
    Show others...
    2005 (English)In: Acta Dermato-Venereologica, ISSN 0001-5555, Vol. 85, no 3, p. 216-220Article 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.

    Keywords
    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
    Show others...
    2006 (English)In: Journal of Plastic, Reconstructive and Aesthetic Surgery, ISSN 1748-6815, Vol. 59, no 3, p. 221-229Article 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.

    Keywords
    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, p. 433-438Article 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.

    Keywords
    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
    Show others...
    2008 (English)In: Wound Repair and Regeneration, ISSN 1067-1927, Vol. 16, no 2, p. 254-265Article 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
  • 12.
    Seifert (Bock), Oliver
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Bayat, Ardeshir
    The Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, UK.
    Geffers, Robert
    Mucosal Immunity, Helmholtz Centre for Infection Research (HCI), Braunschweig, Germany.
    Buer, Jan
    Institute of Medical Microbiology, University Hospital Essen, Essen, Germany.
    Löfgren, Sture
    Department of Clinical Microbiology, County Hospital Ryhov, Jönköping, Sweden.
    Matussek, Andreas
    Department of Clinical Microbiology, County Hospital Ryhov, Jönköping, Sweden.
    Dienus, Kirstin
    Department of Clinical Microbiology, County Hospital Ryhov, Jönköping, Sweden.
    Identification of unique gene expression patterns within different lesional sites of keloids2008In: Wound Repair and Regeneration, ISSN 1067-1927, Vol. 16, no 2, p. 254-265Article in journal (Refereed)
    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.

  • 13.
    Taylor, Adam
    et al.
    Fibrosis and Lung Injury DPU, England.
    Budd, David C.
    Fibrosis and Lung Injury DPU, England.
    Shih, Barbara
    University of Manchester, England.
    Seifert, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Ryhov Hospital, Sweden.
    Beaton, Andrew
    GlaxoSmithKline, England.
    Wright, Tracey
    Fibrosis and Lung Injury DPU, England.
    Dempsey, Maria
    GlaxoSmithKline, England.
    Kelly, Fiona
    GlaxoSmithKline, England.
    Egerton, Julie
    GlaxoSmithKline, England.
    Marshall, Richard P.
    Fibrosis and Lung Injury DPU, England.
    Aston, Nicola
    Fibrosis and Lung Injury DPU, England.
    Bayat, Ardeshir
    University of Manchester, England; University of Manchester, England.
    Transforming Growth Factor Beta Gene Signatures are Spatially Enriched in Keloid Tissue Biopsies and Ex vivo-Cultured Keloid Fibroblasts2017In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 97, no 1, p. 10-16Article in journal (Refereed)
    Abstract [en]

    The keloid lesion is recognised as a spatially heterogeneous mass both in cellular and acellular composition and biological activity. Here, we have utilised a bioinformatic approach to determine whether this spatial heterogeneity is also evident at the molecular level and to identify key upstream regulators of signalling pathways enriched in the lesion in a spatially-restricted manner. Differentially expressed genes (20% change, p amp;lt; 0.05) obtained from microarray datasets derived from whole keloid biopsies and ex vivo-cultured keloid fibroblasts, both from distinct regions of the keloid lesion (leading edge, centre, and top) have been analysed to show that the TGF beta family plays a significant but spatially dependent role in regulation of keloid gene expression. Furthermore, we have identified additional upstream signalling molecules involved in driving keloid biology and provide information on therapeutic targets whose modulation might be expected to lead to significant therapeutic efficacy.

  • 14.
    Thorslund, Kristofer
    et al.
    Karolinska Institute, Sweden.
    Seifert, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Regional Joönköping County, Sweden.
    Nilzen, Karin
    Regional Jonköping County, Sweden.
    Grönhagen, Carina
    Lund University, Sweden.
    Incidence of bullous pemphigoid in Sweden 2005-2012: a nationwide population-based cohort study of 3761 patients2017In: Archives of Dermatological Research, ISSN 0340-3696, E-ISSN 1432-069X, Vol. 309, no 9, p. 721-727Article in journal (Refereed)
    Abstract [en]

    Studies that report the incidence of bullous pemphigoid from validated nationwide population-based registries are rare. The aim of this study was to estimate the incidence of bullous pemphigoid in Sweden 2005-2012. A population-based open cohort study was designed including all patients diagnosed by a dermatologist with bullous pemphigoid (BP) in Sweden from 2005 to 2012 (n = 3761), identified from the National Patient Register (NPR). The diagnosis of bullous pemphigoid in the NPR was recently validated from medical records, histopathological and immunopathological data by our group in a previous study. The average annual incidence of bullous pemphigoid was 7.1/100,000 (95% CI 6.5-7.7). Female to male ratio was 1.2:1, mean age at diagnosis was 78.9 years. The age-specific incidence rate increased markedly after 80 years of age with an incidence peak between 90 and 99 years of age, 81.9/100,000 (95% CI 75.0-89.2). This large nationwide cohort study presents an adjusted incidence of BP of 7.1/100,000 (95% CI 6.5-7.7) in Sweden. The incidence of bullous pemphigoid is higher than expected and bullous pemphigoid is a common disease in the elderly population.

  • 15.
    Tveit, K. S.
    et al.
    Haukeland Hosp, Norway.
    Duvetorp, Albert
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Skanes Univ Sjukhus, Sweden.
    Ostergaard, M.
    Univ Copenhagen, Denmark.
    Skov, L.
    Univ Copenhagen, Denmark.
    Danielsen, K.
    UiT Arctic Univ Norway, Norway; Univ Hosp North Norway, Norway.
    Iversen, L.
    Aarhus Univ Hosp, Denmark.
    Seifert, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Ryhov Hosp, Sweden.
    Treatment use and satisfaction among patients with psoriasis and psoriatic arthritis: results from the NORdic PAtient survey of Psoriasis and Psoriatic arthritis (NORPAPP)2019In: Journal of the European Academy of Dermatology and Venereology, ISSN 0926-9959, E-ISSN 1468-3083, Vol. 33, no 2, p. 340-354Article in journal (Refereed)
    Abstract [en]

    Background There are scarce data in Scandinavia about treatment satisfaction among patients with psoriasis (PsO) and/or psoriatic arthritis (PsA). The number of patients receiving systemic treatment is unknown. Objective To describe patients experience of treatments for PsO/PsA in Sweden, Denmark and Norway, addressing communication with physicians, satisfaction with treatment and concerns regarding treatment options. Methods The NORdic PAtient survey of Psoriasis and Psoriatic arthritis (NORPAPP) asked 22 050 adults (randomly selected from the YouGov panels in Sweden, Denmark and Norway) whether they had PsO/PsA. A total of 1264 individuals who reported physician-diagnosed PsO/PsA were invited to participate in the full survey; 96.6% responded positively. Results Systemic treatment use was reported by 14.6% (biologic: 8.1%) of respondents with PsO only and by 58.5% (biologic: 31.8%) of respondents with PsA. Biologic treatments were more frequently reported by respondents considering their disease severe (26.8% vs 6.7% non-severe) and those who were members of patient organizations (40.7% vs 6.9% non-members). Discussing systemic treatments with their physician was reported significantly more frequently by respondents with PsA, those perceiving their disease as severe (although 35.2% had never discussed systemic treatment with their physician) and those reporting being a member of a patient organization (P amp;lt; 0.05). Many respondents reported health risk concerns and dissatisfaction with their treatment. Of special interest was that respondents aged 45-75 years reported less experience with biologics (8.1%) than those aged 18-44 years (21.5%). The older respondents also reported more uncertainty regarding long-term health risks related to systemic treatments (most [66.7-72.9%] responded do not know when asked about the risk of systemic options). Conclusion It appears likely that substantial numbers of Scandinavians suffering from severe PsO/PsA are not receiving optimal treatment from a patient perspective, particularly older patients. Also, one-third of respondents with severe symptoms had never discussed systemic treatment with a physician.

  • 16.
    Wäster, Petra
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Orfanidis, Kyriakos
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Dermatology and Venerology.
    Eriksson, Ida
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Rosdahl, Inger
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Dermatology and Venerology.
    Seifert, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Ryhov Hospital, Sweden.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    UV radiation promotes melanoma dissemination mediated by the sequential reaction axis of cathepsins-TGF-beta 1-FAP-alpha2017In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 117, no 4, p. 535-544Article in journal (Refereed)
    Abstract [en]

    Background: Ultraviolet radiation (UVR) is the major risk factor for development of malignant melanoma. Fibroblast activation protein (FAP)-alpha is a serine protease expressed on the surface of activated fibroblasts, promoting tumour invasion through extracellular matrix (ECM) degradation. The signalling mechanism behind the upregulation of FAP-alpha is not yet completely revealed. Methods: Expression of FAP-alpha was analysed after UVR exposure in in vitro co-culture systems, gene expression arrays and artificial skin constructs. Cell migration and invasion was studied in relation to cathepsin activity and secretion of transforming growth factor (TGF)-beta 1. Results: Fibroblast activation protein-a expression was induced by UVR in melanocytes of human skin. The FAP-alpha expression was regulated by UVR-induced release of TGF-beta 1 and cathepsin inhibitors prevented such secretion. In melanoma cell culture models and in a xenograft tumour model of zebrafish embryos, FAP-alpha mediated ECM degradation and facilitated tumour cell dissemination. Conclusions: Our results provide evidence for a sequential reaction axis from UVR via cathepsins, TGF-beta 1 and FAP-alpha expression, promoting cancer cell dissemination and melanoma metastatic spread.

  • 17.
    Yu, Haiyan
    et al.
    Department of Dermatology, University of Kiel, Kiel, Germany.
    Bock (Seifert), Oliver
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Bayat, Ardeshir
    School of Biological Sciences, University of Manchester, Manchester, UK.
    Ferguson, Mark WJ
    School of Biological Sciences, University of Manchester, Manchester, UK.
    Mrowietz, Ulrich
    Department of Dermatology, University of Kiel, Kiel, Germany.
    Decreased expression of inhibitory SMAD6 and SMAD7 in keloid scarring2006In: Journal of Plastic, Reconstructive and Aesthetic Surgery, ISSN 1748-6815, Vol. 59, no 3, p. 221-229Article in journal (Refereed)
    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.

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