Global miRNA expression profiles of fibroblast-like synoviocytes in patients with rheumatoid arthritis and osteoarthritis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE91026 | GEO | 2017/10/31
SECONDARY ACCESSION(S): PRJNA356702
REPOSITORIES: GEO
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Project description:Background: The fibroblast-like synoviocyte (FLS) has a central role in rheumatoid arthritis (RA) pathogenesis and its invasive behavior strongly correlates with disease severity and joint damage. Yet, the regulation of FLS invasiveness is incompletely understood. Distal-less homeobox 4 (DLX4) is a transcription factor implicated in cancer cell invasion and metastasis, and we considered that it might also be involved in the regulation of FLS phenotypes. Results: siRNA knockdown of DLX4 significantly reduced RA FLS invasiveness (P=0.028) and migration in the scratch/wound healing assay (P=0.008). RNA sequencing analyses revealed that DLX4 knockdown significantly affected processes and pathways implicated in diverse types of cancer and in cancer biology and cell invasion, including cell cycle, DNA replication, transcription, p53 signal transduction, RHO GTPase signaling, regulation of cytokinesis, as well as response to oxygen levels and to oxidative stress. HMOX1 and SOD2 were among the genes with the most significantly increased expression, while CPNE3 and HADHA were among those with the most significantly decreased expression in FLS knocked down for DLX4 compared with controls. Conclusion: We describe a new role for DLX4 in the regulation of RA FLS behaviors relevant to disease pathogenesis and joint damage, and identify a new transcriptomic signature regulated by this gene. These findings raise the possibility that DLX4, or one of its target genes and pathways may become a target for treatment
2024-09-05 | GSE276473 | GEO
Project description:Invasive pannus, mainly composed of fibroblast-like synoviocytes (FLSs), is a hallmark of rheumatoid arthritis (RA) pathology. Secreted proteins from RA-FLS play key roles in RA invasive pannus. However, RA-FLS-derived secretome associated with invasive pannus has not been systematically investigated. Here, we first identified 843 secreted proteins from RA-FLSs treated with TNFα and IL-1β using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Functional enrichment analysis revealed that 58.5% (493 proteins) of the secretome were associated with pannus-driven RA pathologies. Among them, parallel reaction monitoring (PRM) analysis then identified 16 secreted proteins that were increased in RA SFs (117 samples) than in OA SFs (45 samples). Of them, MYH9 further showed significant positive correlations with RA pathological parameters, such as synovial hyperplasia, increased articular vascularity, and inflammation severity. Molecular and cellular experiments confirmed that MYH9 was expressed in RA-FLSs and more highly under disease-aggravating conditions, and MYH9 depletion significantly defected migration and invasion of RA-FLS in RA pannus. Our study provides a comprehensive resource of RA-FLS-derived secretome, and our results suggest MYH9 that was increased in RA SF and strongly correlated with disease severity as a potential therapeutic target for invasive pannus.
2023-06-30 | PXD041077 | Pride
Project description:The fibroblast-like synoviocyte (FLS) has a central role in rheumatoid arthritis (RA) pathogenesis and its invasive behavior strongly correlates with disease severity and joint damage. Yet, the regulation of FLS invasiveness has been incompletely characterized. The nucleolar and spindle associated protein 1 (NUSAP1) gene has been implicated in cancer cell invasion and outcomes, and we considered that it might also be involved in the regulation of FLS invasiveness. siRNA knockdown of NUSAP1 significantly reduced RA FLS invasiveness (P=0.002) and migration in the scratch/wound healing assay (P=0.024). RNA sequencing analyses revealed that NUSAP1 knockdown significantly affected processes implicated in different types of cancer and in cancer biology, including cell cycle, DNA replication, transcription, RHO GTPase signaling, regulation of cytokinesis and cell metabolism pathways. Among the genes with the most significantly decreased expression in - NUSAP1-KO cells were ARHGAP11A, ANLN, PRC1 and RACGAP1, four genes previously implicated in cancer invasion and migration, and eighteen kinesin family genes, including KIF1c, known to regulate FLS invasion. We describe a new role for NUSAP1 in the regulation of the RA FLS invasiveness and migration, both relevant to disease pathogenesis and joint damage, and identify a new transcriptomic signature regulated by this gene. These findings raise the possibility that NUSAP1, or one of its target genes and pathways may become a new prognostic marker or target for new therapies for RA.
2024-11-21 | GSE276772 | GEO
Project description:Objectives: Epigenetics can influence disease susceptibility and severity. While DNA methylation of individual genes has been explored in autoimmunity, no unbiased systematic analyses have been reported. Therefore, a genome-wide evaluation of DNA methylation loci in fibroblast-like synoviocytes (FLS) isolated from the site of disease in rheumatoid arthritis (RA) was performed. Methods: Genomic DNA was isolated from six RA and five osteoarthritis (OA) FLS lines and evaluated using the Illumina HumanMethylation450 chip. Cluster analysis of data was performed and corrected using Benjamini–Hochberg adjustment for multiple comparisons. Methylation was confirmed by pyrosequencing and gene expression was determined by qPCR. Pathway analysis was performed using the Kyoto Encyclopedia of Genes and Genomes. Results: RA and control FLS segregated based on DNA methylation, with 1859 differentially methylated loci. Hypomethylated loci were identified in key genes relevant to RA, such as CHI3L1, CASP1, STAT3, MAP3K5, MEFV and WISP3. Hypermethylation was also observed, including TGFBR2 and FOXO1. Hypomethylation of individual genes was associated with increased gene expression. Grouped analysis identified 207 hypermethylated or hypomethylated genes with multiple differentially methylated loci, including COL1A1, MEFV and TNF. Hypomethylation was increased in multiple pathways related to cell migration, including focal adhesion, cell adhesion, transendothelial migration and extracellular matrix interactions. Confirmatory studies with OA and normal FLS also demonstrated segregation of RA from control FLS based on methylation pattern. Conclusions: Differentially methylated genes could alter FLS gene expression and contribute to the pathogenesis of RA. DNA methylation of critical genes suggests that RA FLS are imprinted and implicate epigenetic contributions to inflammatory arthritis. Fibroblast-like synoviocyte cell-lines from osteoarthritis (OA) and rheumatoid arthritis (RA) patients.
2013-04-25 | E-GEOD-46364 | biostudies-arrayexpress
Project description:TNF-like ligand 1A (TL1A) is a member of TNF receptor superfamily and involved in the pathogenesis of autoimmune diseases by inducing apoptosis via intracellular death domain or promoting inflammation through the activation of NFκB by binding to its specific receptor death receptor 3 (DR3). Meanwhile, decoy receptor 3 (DcR3) competitively binds soluble TL1A in addition to Fas-ligand (FasL) and LIGHT and inhibits the signaling of TL1A via DR3. DcR3 overexpressed in rheumatoid synovial fibroblasts (RA-FLS) stimulated with inflammatory cytokines such as TNFα or IL-1β inhibits Fas-induced apoptosis. In contrast, DcR3 inhibited cell proliferation induced by inflammatory cytokines via membrane-bound TL1A expressed on RA-FLS. Therefore, TL1A-DcR3/DR3 signaling may be involved in the pathogenesis of RA by modulating apoptosis and proliferation of RA-FLS. We hypothesized that TL1A regulates the gene expression in RA-FLS. We used to search for genes in which expression in RA-FLS is regulated by the ligation of TL1A.
2014-12-10 | GSE63995 | GEO
Project description:Homo sapiens microRNAs (miRNAs) are invovolved in the regulation of multiple cellular processes and have been linked to many conditions in humans, including rheumatic diseases such as rheumatoid arthritis (RA). Here, we used high throughput expression analysis to assess the overall miRNA expression level in FLS isolated from RA patients in comparison with miRNA expressed in FLS from osteoarthritic (OA) patients. FLS isolated from synovial biopsies from 4 RA and 4 OA patients were cultivated for 4 passages. Cells were lysed and RNA purified (Trizol). Then miRNA expression was performed using the Qiagen Human miRNome miScript miRNA PCR Array (V16.0, 384-well) profiling the expression of the 1066 most abundantly expressed and best characterized miRNA sequences in the human miRNA genome (miRNome) as annotated in miRBase Release 16 (www.mirbase.org).
2015-09-01 | E-GEOD-72564 | biostudies-arrayexpress
Project description:Despite recent advances, rheumatoid arthritis (RA) patients remain refractory to therapy. Dysregulated overproduction of angiopoietin-like protein 4 (ANGPTL4) is thought to contribute to the disease development. ANGPTL4 was initially identified as a regulator of lipid metabolism, which is hydrolyzed to N-terminal and C-terminal (cANGPTL4) fragments in vivo. cANGPTL4 is involved in several non-lipid-related processes, including angiogenesis and inflammation. This study revealed that the level of ANGPTL4 was markedly elevated in the sera and synovial tissues from patients with RA versus controls. The administration of a neutralizing antibody against cANGPTL4 (anti-cANGPTL4 Ab) resulted in the inhibition of inflammatory processes and bone loss in animal models of collagen-induced arthritis and adjuvant-induced arthritis (AIA). Transcriptomic and proteomic profiling of synovial tissues from an AIA model indicated that the anti-cANGPTL4 Ab inhibited fibroblast-like synoviocyte (FLS) immigration and inflammatory-induced osteoclastogenesis. Mechanistically, the anti-cANGPTL4 Ab has been shown to inhibit TNF-α-induced inflammatory cascades in RA-FLS through the sirtuin 1/nuclear factor-κB signaling pathway. Moreover, the anti-cANGPTL4 Ab was found to block FLS invasion- and immigration-induced osteoclast activation. Collectively, these findings identify ANGPTL4 as a prospective biomarker for the diagnosis of RA, and targeting cANGPTL4 should represent a potential therapeutic strategy.
2024-10-24 | GSE276556 | GEO
Project description:Homo sapiens microRNAs (miRNAs) are invovolved in the regulation of multiple cellular processes and have been linked to many conditions in humans, including rheumatic diseases such as rheumatoid arthritis (RA). Here, we used high throughput expression analysis to assess the overall miRNA expression level in FLS isolated from RA patients in comparison with miRNA expressed in FLS from osteoarthritic (OA) patients.
2015-09-01 | GSE72564 | GEO
Project description:Huntingtin-interacting protein 1 Related (HIP1R) protein, shares some function similarities with HIP1, and HIP1 regulates arthritis and RA fibroblast-like synoviocytes (FLS) invasiveness. Therefore, we hypothesized that HIP1R might be involved in the regulation of FLS phenotypes and molecular processes relevant to RA. siRNA was used to knockdwon HIP1R, HIP1 or control in RA FLS followed by cell studies for invasion in Matrigel, migration, proliferation and adhesion. RNA was sequenced and analyzed. HIP1R knockdown significantly reduced RA FLS invasiveness and migration (P<0.05). The DEGs in siRNA HIP1R had an enrichment for GO processes “astrocyte and glial cell projection”, “small GTPase signaling” and “PDGFR signaling”. The most significantly DEGs had decreased expression in siRNA HIP1R and included AKT1S1, GABBR2, GPR56, and TXNDC12. siRNA HIP1 RA FLS had an enrichment for the “Rap1 signaling pathway” and “Growth factor receptor binding”. The most significantly DEGs in HIP1 siRNA included FGF2, PGF, and SLC39A8. HIP1R and HIP1 DEG lists had a greater than expected number of similar genes (P=0.0015), suggesting that, despite the major differences detected, both have partially overlapping functions in RA FLS. The most significant DEGs in both HIP1R and HIP1 analyses are involved in cancer cell behaviors and outcomes. HIP1R is a new gene implicated in RA FLS invasiveness and migration, and regulates unique pathways and cell processes relevant to both RA as well as cancer biology. Our study provides new insight into processes implicated in FLS invasiveness, which is relevant for joint damage in RA, and identify new potential gene targets for FLS-specific treatments.
2024-11-21 | GSE278613 | GEO
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
2014-01-09 | E-GEOD-49604 | biostudies-arrayexpress