Dataset Information

Expression of chemokines CXCL4 and CXCL7 by synovial macrophages defines an early stage of rheumatoid arthritis.

ABSTRACT:

Background and objectives

For our understanding of the pathogenesis of rheumatoid arthritis (RA), it is important to elucidate the mechanisms underlying early stages of synovitis. Here, synovial cytokine production was investigated in patients with very early arthritis.

Methods

Synovial biopsies were obtained from patients with at least one clinically swollen joint within 12?weeks of symptom onset. At an 18-month follow-up visit, patients who went on to develop RA, or whose arthritis spontaneously resolved, were identified. Biopsies were also obtained from patients with RA with longer symptom duration (>12?weeks) and individuals with no clinically apparent inflammation. Synovial mRNA expression of 117 cytokines was quantified using PCR techniques and analysed using standard and novel methods of data analysis. Synovial tissue sections were stained for CXCL4, CXCL7, CD41, CD68 and von Willebrand factor.

Results

A machine learning approach identified expression of mRNA for CXCL4 and CXCL7 as potentially important in the classification of early RA versus resolving arthritis. mRNA levels for these chemokines were significantly elevated in patients with early RA compared with uninflamed controls. Significantly increased CXCL4 and CXCL7 protein expression was observed in patients with early RA compared with those with resolving arthritis or longer established disease. CXCL4 and CXCL7 co-localised with blood vessels, platelets and CD68(+) macrophages. Extravascular CXCL7 expression was significantly higher in patients with very early RA compared with longer duration RA or resolving arthritis

Conclusions

Taken together, these observations suggest a transient increase in synovial CXCL4 and CXCL7 levels in early RA.

SUBMITTER: Yeo L

PROVIDER: S-EPMC4819606 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Publications

Expression of chemokines CXCL4 and CXCL7 by synovial macrophages defines an early stage of rheumatoid arthritis.

Yeo L L Adlard N N Biehl M M Juarez M M Smallie T T Snow M M Buckley C D CD Raza K K Filer A A Scheel-Toellner D D

Annals of the rheumatic diseases 20150409 4

<h4>Background and objectives</h4>For our understanding of the pathogenesis of rheumatoid arthritis (RA), it is important to elucidate the mechanisms underlying early stages of synovitis. Here, synovial cytokine production was investigated in patients with very early arthritis.<h4>Methods</h4>Synovial biopsies were obtained from patients with at least one clinically swollen joint within 12 weeks of symptom onset. At an 18-month follow-up visit, patients who went on to develop RA, or whose arthri ...[more]

PMID: 25858640

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Project description:OBJECTIVE:Currently, there are no reliable biomarkers for predicting therapeutic response in patients with rheumatoid arthritis (RA). The synovium may unlock critical information for determining efficacy, since a reduction in the numbers of sublining synovial macrophages remains the most reproducible biomarker. Thus, a clinically actionable method for the collection of synovial tissue, which can be analyzed using high-throughput strategies, must become a reality. This study was undertaken to assess the feasibility of utilizing synovial biopsies as a precision medicine-based approach for patients with RA. METHODS:Rheumatologists at 6 US academic sites were trained in minimally invasive ultrasound-guided synovial tissue biopsy. Biopsy specimens obtained from patients with RA and synovial tissue from patients with osteoarthritis (OA) were subjected to histologic analysis, fluorescence-activated cell sorting, and RNA sequencing (RNA-seq). An optimized protocol for digesting synovial tissue was developed to generate high-quality RNA-seq libraries from isolated macrophage populations. Associations were determined between macrophage transcriptional profiles and clinical parameters in RA patients. RESULTS:Patients with RA reported minimal adverse effects in response to synovial biopsy. Comparable RNA quality was observed from synovial tissue and isolated macrophages between patients with RA and patients with OA. Whole tissue samples from patients with RA demonstrated a high degree of transcriptional heterogeneity. In contrast, the transcriptional profile of isolated RA synovial macrophages highlighted different subpopulations of patients and identified 6 novel transcriptional modules that were associated with disease activity and therapy. CONCLUSION:Performance of synovial tissue biopsies by rheumatologists in the US is feasible and generates high-quality samples for research. Through the use of cutting-edge technologies to analyze synovial biopsy specimens in conjunction with corresponding clinical information, a precision medicine-based approach for patients with RA is attainable.

Project description:ObjectiveRheumatoid arthritis (RA) is one of the most prevalent inflammatory arthritis worldwide. However, the genes and pathways associated with macrophages from synovial fluids in RA patients still remain unclear. This study aims to screen and verify differentially expressed genes (DEGs) related to identifying candidate genes related to synovial macrophages in rheumatoid arthritis by bioinformatics analysis.MethodsWe searched the Gene Expression Omnibus (GEO) database, and GSE97779 and GSE10500 with synovial macrophages expression profiling from multiple RA microarray dataset were selected to conduct a systematic analysis. GSE97779 included nine macrophage samples from synovial fluids of RA patients and five macrophage samples from primary human blood of HC. GSE10500 included five macrophage samples from synovial fluids of RA patients and three macrophage samples from primary human blood of HC. Functional annotation of DEGs was performed, including Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Protein-protein interaction (PPI) network of DEGs was established using the STRING database. CytoHubba was used to identify hub genes. MCODE was used to determine gene clusters in the interactive network.ResultsThere were 2638 DEGs (1425 upregulated genes and 1213 downregulated ones) and 889 DEGs (438 upregulated genes and 451 downregulated ones) selected from GSE97779 and GSE10500, respectively. Venn diagrams showed that 173 genes were upregulated and 106 downregulated in both two datasets. The top 10 hub genes, including FN1, VEGFA, HGF, SERPINA1, MMP9, PPBP, CD44, FPR2, IGF1, and ITGAM, were identified using the PPI network.ConclusionThis study provides new insights for the potential biomarkers and the relevant molecular mechanisms in RA patients. Our findings suggest that the 10 candidate genes might be used in diagnosis, prognosis, and therapy of RA in the future. However, further studies are required to confirm the expression of these genes in synovial macrophages in RA and control specimen.

Dataset Information

Expression of chemokines CXCL4 and CXCL7 by synovial macrophages defines an early stage of rheumatoid arthritis.

Background and objectives

Methods

Results

Conclusions

Publications

Expression of chemokines CXCL4 and CXCL7 by synovial macrophages defines an early stage of rheumatoid arthritis.

Similar Datasets

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