MSc (Med), Faculty of Health Sciences, University of the Witwatersrand / Introduction: Systemic sclerosis (SSc) is a complex autoimmune disease characterised by autoantibody release, leading to microvascular injury, fibroblast activation and increased production of collagen. The genetics of SSc is complex with many genes implicated in the development and maintenance of the extracellular matrix (ECM). The main aim of this study was to test for differential expression of matrix metalloproteinase 1 (MMP1), tissue inhibitor of metalloproteinase 1 (TIMP1) and hepatocyte growth factor (HGF) in SSc patients compared to healthy control individuals and to assess whether the differential expression of these genes could have an impact on clinical features of the disease. Methods: Two skin biopsies were analysed for each of 16 black SSc patients, one from clinically involved skin (lateral forearm) and one from clinically uninvolved skin (back). One skin sample was obtained from 15 ethnically matched control individuals. The differential expression of MMP1, TIMP1 and HGF in the clinically involved and uninvolved patient samples would be compared to control individuals using relative quantification polymerase chain reaction (qPCR). The gene expression profiles were then compared to specific clinical features to deduce whether any of the gene expression profiles is correlated with the manifestation of specific clinical features.
Results: MMP1 gene expression was significantly decreased in SSc patients for both involved (p=0.0004) and uninvolved skin (p=0.0004) compared to controls. Conversely, TIMP1 gene expression was significantly increased in SSc patients at both sites compared to controls (p=<0.00001 for both comparisons). A trend of significance was observed for the difference in TIMP1 expression between the involved an uninvolved skin within the patients (p=0.05) with a greater increase in involved skin. HGF had increased gene expression in the patients compared to controls for involved and uninvolved skin (p=0.002 and 0.004, respectively). The difference in gene expression between the involved and uninvolved biopsies was not significant for either MMP1 or HGF (p=0.87 and 0.83, respectively). The only correlates that may have a biological significance are HGF in involved skin correlated with disease activity (r=0.60; p=0.013) and HGF in uninvolved skin
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correlated with skin score (MRSS) with r=0.50 and p=0.048. With regards to the categorical data, two marginally significant observations were found, once again with HGF, which was found to be associated with gender in involved skin (p=0.037) and renal disease in uninvolved skin (0.031). Conclusion: The relative under expression of MMP1 and over expression of TIMP1 reflect the pro-fibrotic state of scleroderma skin. The over expression of HGF suggests that HGF may play a compensatory anti-fibrotic role, although this is not sufficient to overcome the pro-fibrotic state of the skin. This study provides supporting evidence to debunk the myth of uninvolved skin in SSc patients. The altered expression of MMP1, TIMP1 and HGF in the clinically uninvolved skin of SSc patients suggests that all subcutaneous tissue is affected, although to a greater extent in the clinically involved skin of the patients.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/8699 |
| Date | 14 September 2010 |
| Creators | Frost, Jacqueline Michelle |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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