Abstract
Systemic sclerosis (SSc) is a complex, heterogeneous connective tissue disease, characterized by fibrosis and ECM deposition in skin and internal organs, autoimmunity, and changes in the microvasculature. Profiling of circulating miRNAs in serum has been found to be changed in pathological states, creating new possibilities for molecular diagnostics as blood-based biomarkers. This study was designed to identify miRNAs that are differentially expressed in SSc and might be potentially contributing to the disease etiopathogenesis or be used for diagnostic purposes. Thus, we compared the expression pattern of multiple miRNAs in serum of 10 SSc patients to 6 healthy controls using microarray analysis, and RT-qPCR to confirm the obtained results. In addition, bioinformatics analysis was performed to explore miRNAs target genes and the signaling pathways that may be potentially involved in SSc pathogenesis. Our study shows a different expression of 15 miRNAs in SSc patients. We identified that miR-4484, located on chromosome 10q26.2, was an 18-fold up-regulated in SSc patients compared to a control group. Bioinformatics analysis of the miR-4484 target genes and the signaling pathways showed that it might be potentially involved in the TGF-β signaling pathway, ECM-receptor interaction, and metalloproteinases expression. Based on the chromosomal location, the most interesting target gene of miR-4484 may be MMP-21. We found that the expression of MMP-21 significantly increased in SSc patients compared to healthy subjects (P < 0.05). Our results suggest that miR-4484, and MMP-21 might be novel serum biomarkers that may correspond to pathological fibrosis in SSc, but it needs to be validated in further studies.
Highlights
Systemic sclerosis (SSc) is a complex, heterogeneous connective tissue disease (CTD), characterized by immune abnormalities, microvasculopathy with capillary loss and excessive extracellular deposition with subsequent fibrosis of the skin and internal organs[1]
We performed bioinformatics analysis to explore target genes for differentially expressed miRNAs, their possible signaling pathways potentially involved in SSc pathogenesis, and a gene ontology term enrichment analysis to determine signaling pathways and biological processes associated with target genes
Using Genemania tool[9], we found the interactions between the target genes, for example, YAP1, which limit transforming growth factor-β (TGF-β) signaling along with TAZ, PTPN14, which is a negative regulator of YAP activity, AGO3, which plays a role in RNA interference, CTNNB1 – in Wnt signaling pathway and epithelial-to-mesenchymal transition or TEAD1 – in smooth muscle development (Fig. 4)[12]
Summary
Systemic sclerosis (SSc) is a complex, heterogeneous connective tissue disease (CTD), characterized by immune abnormalities, microvasculopathy with capillary loss and excessive extracellular deposition with subsequent fibrosis of the skin and internal organs[1]. The pathological steps in the disease process are unclear They seem to include an autoimmune attack, vascular damage, and tissue inflammation that trigger abnormal activation of fibroblasts with enhanced collagen deposition into the extracellular matrix (ECM)[4]. Many reports suggest that miRNAs and their targets are aberrantly expressed in skin and fibroblasts of SSc patients compared to healthy tissues, making them potential novel players in SSc fibrosis[4] They are thought to regulate numerous fibrotic-related genes; their exact role in SSc pathogenesis remains unclear, and studies with a broad profiling of circulating miRNAs are scarce[11]. We performed bioinformatics analysis to explore target genes for differentially expressed miRNAs, their possible signaling pathways potentially involved in SSc pathogenesis, and a gene ontology term enrichment analysis to determine signaling pathways and biological processes associated with target genes
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