Serum microRNAs in Systemic Sclerosis, Associations with Digital Vasculopathy and Lung Involvement

Abstract

Background and aims: Systemic sclerosis (SSc) is an autoimmune, rare multisystem chronic disease that is still not well-understood aetiologically and is challenging diagnostically. In the literature, there are ever-increasing assumptions regarding the epigenetic mechanisms involved in SSc development; one of them is circulating microRNAs. Many of them regulate TLR pathways and are significant in autoimmune balance. The aim of this study was to determine profile expression of selected microRNAs in SSc patients, including miR-126, -132, -143, -145, -155, -181a, -29a and -3148, in comparison to healthy controls. Methods: Serum microRNAs were isolated from 45 patients with SSc and 57 healthy donors (HC). Additionally, SSc patients were considered in the aspect of disease subtype, including diffuse systemic sclerosis (dcSSc) and limited systemic sclerosis (lcSSc). Results: miR-3148 was detected neither in the serum of HC nor in SSc patients. All of the rest of the analyzed microRNAs, excluding miR-126, miR-29a and miR-181a, were significantly upregulated in SSc patients in comparison to HC. However, miR-181a has been revealed only in the serum of patients with lcSSc but not dcSSc. Moderate positive correlations between the transfer factor of the lung for carbon monoxide (TLCO) and miR-126 and miR-145 were observed. A significant correlation has been found between serum miR-143 level and forced vital capacity (FVC). SSc patients with FVC ≤ 70% were characterized by significantly lower levels of miR-143 compared to patients with normal FVC. Additionally, the expression of miR-132 was significantly higher in dcSSc subgroup with detected active lung lesions compared to dcSSc patients with fibrotic lesions. Patients with an early scleroderma pattern of microangiopathy seen on nailfold video-capillaroscopy (NVC) revealed higher expression of miR-155 in serum than those with a late pattern. Conclusions: The expression profile of circulating cell-free miRNAs is significantly changed in the serum of SSc patients compared to healthy individuals. Downregulation of miRNA-181a and overexpression of miR-132, miR-143, miR-145 and miR-155 in serum may be significant in SSc in the context of biomarkers.

Prognostic factors in systemic sclerosis

“…Patients with systemic sclerosis and FVC ≤ 70% were found to show decreased levels of miR-143 in comparison to patients having normal FVC levels. Also, miR-132 expression was shown to be higher in the dcSSc subgroup with detected active lung lesions compared to dcSSc patients with fibrotic lesions [43].…”

“…Recent studies have confirmed positive correlations between serum miRNA expression levels and the diagnosis of systemic sclerosis. Among other findings, reduced levels of miRNA-181a and miR-138, and overexpression of miR-126, miR-139-5p, miR-618, miR-132, miR-143, miR-145 and miR-155 have been detected in the serum of patients [40][41][42][43][44]. Also, a link has been shown between the pulmonary complications of SSc and the expression of individual miRNAs.…”

Biomarkers in Systemic Sclerosis: An Overview

“…Cytokeratin 17 (CK17), marginal zone protein B1 (MZB1), and leucine-rich α2-glycoprotein-1 (LRG1) appear to be potential biomarkers for SSc, with CK17 negatively associated with disease severity and higher values of CK17 protective [37,[59][60][61][62][63][64][65][66][67]. A potential therapeutic target could be endostatin, which is associated with vascular manifestations in SSc and is specifically elevated in progressive SSc; it has been considered a marker of disease severity [38,[62][63][64][65][66][67].…”

“…The chemokine CC2 (CCL2) also appears to be involved in the development of fibrosis in SSc [39][40][41][42]62]. MicroRNAs (miRNAs) are short nucleotide sequences involved in cellular regulation [37,38]. The miR-138 and miR-27a microRNAs suppress major pathways involved in epithelial-to-mesenchymal cell transition and subsequent fibrosis [37,38,45,[60][61][62][63][64][65][66][67].…”

“…Antinuclear antibodies (ANA) are present in more than 90% of SSc patients, along with anticentromere, anti-Th/To, and anti-topoisomerase I antibodies, which are considered the classic biomarkers present in 60% of SSc patients and help to define precise clinical classifications [4,7,[29][30][31][32][33][34][35][36][37]. Other autoantibodies, such as those directed against the endothelium or fibroblasts, against angiotensin II type 1 receptor, endothelin-1 type A receptor, platelet-derived growth factor receptor (anti-PDGFR), and extracellular matrix (ECM) proteins [16][17][18][19][20][38][39][40][41][42][43][44][45] are also found in SSc patients. More complex autoantibody systems against G-protein-coupled receptors, growth factors, and respective receptors have also been described in SSc [21,[45][46][47][48][49].…”