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Global miRNA expression profiles of fibroblast-like synoviocytes in patients with rheumatoid arthritis and osteoarthritis

ABSTRACT: Fibroblast-like synoviocyte (FLS) constitutes a major cell subset of rheumatoid arthritis (RA) joint. Dysregulation of microRNAs (miRNAs) contributes to FLS activation in the context of chronic inflammation. However, functional association of the miRNAs-targets relationships characterizing FLS phenotypes in RA has not been fully elucidated yet. Thus, we uncovered the novel miRNA-target interactions characterizing pathologic phenotypes of RA-FLS. We performed microarray analyses of miRNA in RA- and osteoarthritis (OA) FLS with or without interleukin-1β (IL-1β) stimulation. The miRNA-target prediction and network model-ing were performed using TargetScan and Cytoscape. Identified miRNA-target relationships and their cellular functions were validated in vitro.

ORGANISM(S): Homo sapiens

PROVIDER: GSE91026 | GEO | 2017/10/31

SECONDARY ACCESSION(S): PRJNA356702

REPOSITORIES: GEO

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Project description:Rheumatoid synoviocytes, which consist of fibroblast-like synoviocytes (FLS) and synovial macrophages (SM), are crucial for the progression of rheumatoid arthritis (RA). Particularly, FLS of RA patients (RA-FLS) exhibit invasive characteristics reminiscent of cancer cells, destroying cartilage and bone, although it remains unresolved how RA-FLS exhibit invasive phenotype. RA-FLS and SM originate differently from mesenchymal and myeloid cells, respectively, but share many pathologic functions. However, the molecular signatures and biological networks representing the distinct and shared features of the two cell types are unknown. Presently, we performed global transcriptome profiling of FLS and SM obtained from RA and osteoarthritis patients. By comparing the transcriptomes, we identified distinct molecular signatures and cellular processes defining invasiveness of RA-FLS and pro-inflammatory properties of RA synovial macrophages (RA-SM), respectively. Interestingly, under interleukin1β-stimulated condition, RA-FLS newly acquired pro-inflammatory signature mimicking RA-SM without losing invasive properties. We next reconstructed a network model that delineates the shared, RA-FLS-dominant (invasive), and RA-SM-dominant (inflammatory) processes. From the network model, we selected 13 genes, including POSTN and TWIST1, as novel regulator candidates responsible for FLS invasiveness. Of note, POSTN and TWIST1 expressions were elevated in independent RA-FLS and were further instigated by interleukin1β. In vitro functional assays demonstrated the requirement of POSTN and TWIST1 for migration and invasion of RA-FLS stimulated with interleukin1β. Taken together, our systems approach to rheumatoid synovitis provides a basis for identifying novel regulators responsible for pathological features of RA-FLS and RA-SM, demonstrating how a certain type of cells acquires functional redundancy under chronic inflammatory conditions. To identify molecular signatures of FLS and MLS in RA joints, we isolated FLS from synovial tissues of RA and osteoarthritis (OA) patients, obtained synovial macrophages from synovial fluid of RA patients, and differentiated control macrophages from peripheral blood of healthy subjects. Also, we stimulated FLS with IL1β, and then analyzed gene expression profiles of both IL1β-stimulated RA-FLS and OA-FLS

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Global miRNA expression profiles of fibroblast-like synoviocytes in patients with rheumatoid arthritis and osteoarthritis

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