Abstract
BackgroundThe etiology of rheumatoid arthritis (RA) remains poorly understood. Early and accurate diagnosis still difficult to achieve. Inflammatory related molecules released into the circulation such cytokines and exosome-derived microRNAs (exomiRNAs) could be good candidates for early diagnosis of autoimmune diseases. We sought to discover a serum biomarker panel for the early detection of RA based on exomiRNAs and inflammatory markers.MethodsA 179 miRNAs-microarray panel was analyzed in a pilot study (4 early RA and 4 controls). Validation of deregulated exomiRNAs was performed in a larger cohort (24 patients with early RA and 24 controls). miRNet software was used to predict exomiRNA gene-targets interactions. Potentially altered pathways were analyzed by Reactome pathway database search. STRING database was used to predict protein-protein interaction networks. Enzyme-linked immunosorbent assay was used to measure serum levels of sTWEAK and sCD163. Signature biomarker candidates were statistical analyzed.ResultsWe detected 11 differentially expressed exomiRNAs in early RA pilot study. Validation analysis revealed that 6/11 exomiRNAs showed strong agreement with the pilot microarray data (exomiR-144-3p, -25-3p, -15a-5p, -451a, -107 and -185-5p). sTWEAK and sCD163 biomarkers were significantly elevated in the serum of patients with early RA. Receiver operating characteristic (ROC) analysis showed that the best panel to diagnose early RA contained exomiR-451a, exomiR-25-3p and sTWEAK, and could correctly classify 95.6% of patients, with an area under the ROC curve of 0.983 and with 100% specificity and 85.7% sensitivity. The YWHAB gene was identified as a common target of the putative miRNA-regulated pathways.ConclusionA novel serum biomarker panel composed of exomiR-451a, exomiR-25-3p and serum levels of sTWEAK may have use in the early clinical diagnosis of RA. A new predicted exomiRNA-target gene YHWAB has been identified and may have a relevant role in the development of RA.
Highlights
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and degradation of the peripheral joints [1]
Isolated serum exosomes from an early RA patient sample was treated with osmium tetroxide to stain lipid-bilayer [32] to test the purity and size by transmission electron microscopy (TEM)
In order to comply with the guidelines of the International Society of Extracellular Vesicles [34], we extracted protein from isolated exosomes and from monocytic cell line THP-1, as a whole cell protein control and, tested for the presence of selected exosome markers by using western blot analysis
Summary
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and degradation of the peripheral joints [1]. Given the heterogeneity in clinical RA manifestations and the variability of therapeutic response [2], the identification of early stage disease is essential to halt/slow its evolution. Biomarkers capable of guiding early detection for personalized treatment are urgently needed in RA. The etiology of rheumatoid arthritis (RA) remains poorly understood. And accurate diagnosis still difficult to achieve. Inflammatory related molecules released into the circulation such cytokines and exosome-derived microRNAs (exomiRNAs) could be good candidates for early diagnosis of autoimmune diseases. We sought to discover a serum biomarker panel for the early detection of RA based on exomiRNAs and inflammatory markers
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