Cellular Communication Network Factor 3 contributes to the pathological process of rheumatoid arthritis via promoting cell senescence in synovial cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE271643 | GEO | 2024/11/26
REPOSITORIES: GEO
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Project description:Cellular Communication Network Factor 3 (CCN3) is a secreted protein. It belongs to the CCN family of regulatory proteins, which play essential roles in various cellular processes. In this study, we investigated the functional characteristics of CCN3 in rheumatoid arthritis. We found CCN3 is involved in cellular senescence and osteoclastgenesis of macrophage in vitro. To understand this mechanism, CCN3 is were added to Macrophage and their responses were examined by bulk-RNA analysis.
2024-11-26 | GSE272743 | GEO
Project description: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.
2017-10-31 | GSE91026 | 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:Genome-wide association studies have reported more than 100 risk loci for rheumatoid arthritis, and there loci have been shown to be enriched in immune cell-specific enhancers, we add Synovial fibroblasts (FLS), the local stromal cells of joints to this analysis. We integrated ChIP-seq, Hi-C, Capture Hi-C, ATAC-seq and RNA-seq datasets from FLS , with genetic fine-mapping of RA loci. From this we identified putative casual variants, enhancers and genes for 30-60% of RA loci and demonstrated that FLS regulatory elements accounts for up to 24% of RA heritability. We also examined the effects of TNF stimulation on the chromatin landscape of FLS, and we found there are significant alterations in the organization of topologically associated domains, chromatin interactions and the expression of several putative causal genes.
2020-12-20 | GSE163548 | GEO
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: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:Objective: Fibroblast-like synovial cells (FLS) have multilineage differentiation potential including osteoblasts. We aimed to investigate the role of microRNAs during the osteogenic differentiation of rheumatoid arthritis (RA)-FLS. Methods: MicroRNA(miRNA) array analysis was performed to investigate the differentially expressed miRNAs during the osteogenic differentiation. Expression of miR-218-5p (miR-218) during the osteogenic differentiation was determined by quantitative real-time PCR. Transfection with miR-218 precursor and inhibitor were used to confirm the targets of miR-218 and to analyse the ability of miR-218 to induce osteogenic differentiation. Results: The miRNA array revealed that 12 miRNAs were up-regulated and 24 miRNAs were down-regulated after osteogenic differentiation. We observed that miR-218 rose in the early phase of osteogenic differentiation and then decreased. Micro array analysis revealed the mir-218 modulate the expression of ROBO1 in RA-FLS. The induction of miR-218 in RA-FLS decreased ROBO1 expression, and promoted osteogenic differentiation.
2018-03-26 | GSE111946 | GEO
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: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:The variant rs26232, in the first intron of the C5orf30 locus, has recently been associated with both risk of developing rheumatoid arthritis (RA) and severity of tissue damage. The biological activities of human C5orf30 are unknown, and neither the gene nor protein show significant homology to any other characterized human sequences. The C5orf30 gene is present only in vertebrate genomes with a high degree of conservation implying a central function in these organisms. Here we report that C5orf30 is highly expressed in the synovium of RA patients compared with control synovial tissue, and that it is predominately expressed by synovial fibroblast (RASF) and macrophages in the lining and sublining layer of the tissue. These cells play a central role in the initiation and perpetuation of RA and are implicated in cartilage destruction. RASFs lacking C5orf30 exhibit increased cell migration and invasion in vitro and gene-profiling following C5orf30 inhibition confirmed upregulation of genes involved in cell migration, adhesion, angiogenesis, and immune and inflammatory pathways. Importantly, loss of C5orf30 contributes to the pathology of inflammatory arthritis in vivo, since inhibition of C5orf30 in the collagen-induced arthritis model markedly accentuated joint inflammation and tissue damage. Our study reveal C5orf30 to be a novel negative regulator of tissue damage in RA and this may act by modulating the autoaggressive phenotype that is characteristic of RASFs. Rheumatoid arthritis (RA) is a chronic, autoimmune, inflammatory disease that affects synovial joints. A key characteristic of RA is hyperplasia of fibroblast-like synoviocytes (FLS) which develop a stable, auto-aggressive phenotype that augments tissue destruction. It is unknown how this phenotype is stably maintained; however, epigenetic changes have been implicated. Histone deacetylation is one proposed method; a process controlled by histone deacetylases (HDACs). However, there have recently been reports publishing conflicting data regarding the expression of HDACs in RA synovium and FLS. The objective of this thesis is to determine the role of HDACs in regulating the auto-aggressive phenotype of RA through studies in FLS and in mice. Real time-quantitative PCR was used to assess the levels of HDAC1-11 in RA compared to osteoarthritis (OA) FLS. Immunohistochemistry and western blotting were used to assess protein expression of HDAC1 in RA and OA synovial tissue and FLS. HDAC1 was found to be overexpressed in RA compared to OA. HDAC1 was knocked down in RA FLS, then cell proliferation, migration and invasion were assessed by using tritiated thymidine, a scratch assay and a Matrigel invasion assay respectively. All three functions were significantly reduced following HDAC1 knockdown. An Illumina BeadChip (47,000 transcripts) was used to analyse global gene expression changes after knockdown. This revealed significant gene changes in important functional clusters, such as proliferation and migration. HDAC1 knockout is embryonic lethal in mice, so the in vivo role of HDAC1 was investigated in a mouse model of collagen-induced arthritis (CIA) using in vivo siRNAs. Clinical scores of CIA were measured daily and HDAC1 knockdown mice showed a significantly reduced clinical score compared to controls, comparable to dexamethasone-treated mice. The bones were analysed using a microCT scanner and histology. Knocking down HDAC1 showed reduced bone erosion, joint inflammation and cartilage degradation compared to controls. Overall, this study shows that HDAC1 is dysregulated in RA and it has a significant role in the autoaggressive phenotype shown in RA FLS and collagen-induced arthritis. The novel data shown in this thesis demonstrates that inhibiting HDAC1 may provide a powerful new target for treating RA. Three independent patient RASF samples were analysed in this study for each siRNA gene knockdown. Also a non targerting control siRNA was also used for each of the patient RASFs
2015-08-22 | E-GEOD-72258 | biostudies-arrayexpress