Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

MYD88 dimerization controls the proliferative, invasive, and pro-inflammatory responses of synovial fibroblasts from rheumatoid arthritis patients

ABSTRACT: Purpose: We analyzed RNA-seq from rheumatoid arthritis synovial fibroblats and osteoarthritis syniovial fibroblast patients. Our goal was to evaluate the gene expression signatures after treatment with the MyD88 dimerization onhibitor ST2825 and identify its therapeutic potential. Methods: We analyzed bulk RNA-seq from RA synovial fibroblasts in diferent conditions: Untreated, ST2825-treated, LPS-treated, LPS+ST2825-treated. Aditionally, we analyzed bulk RNA-seq from OA synovial fibroblatss as a control. Collection of RNA was performed after 24 h of treatment and samples were sequenced to determine transcriptional changes and regulated processes. Results: paired-end reads were mapped to the homo sapiens GRCh37 genome assembly. RNA levels were normalized by RPKM and student's t-test. Conclusion: The aggressiveness of the RA SFs, in terms of their proliferation, invasiveness, and increased expression of pain and inflammation mediators was decreased by ST2825. Our data strongly suggest that targeting MyD88 dimerization could mitigate joint inflammation in RA SFs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE217012 | GEO | 2023/09/27

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Targeting MyD88 Downregulates Inflammatory Mediators and Pathogenic Processes in PBMC From DMARDs-Naïve Rheumatoid Arthritis Patients

Project description:Purpose: We analyzed RNA-seq from peripheral blood mononuclear cells (PBMC) in DMARDs-naïve RA patients and healthy subjects. Our goal was to evaluate the transcriptional profiles of ST2825-treated PBMC to identify its therapeutic potential. Methods: We analyzed bulk RNA-seq from peripheral blood mononuclear cells (PBMC) in DMARDs-naïve RA patients after stimulation with LPS and IL-1β, PBMC were treated with the MyD88 chemical inhibitor, ST2825. Collection of RNA was performed after 24 h of treatment and samples were sequenced to determine transcriptional changes and regulated processes in treated PBMC. Results: paired-end reads were mapped to the hg19 human genome assembly. RNA levels were normalized using DESeq. We identified 796 differentially expressed (DE) genes by 2-fold change (p<0.05) between RA patients and healthy subjects. Our analysis revealed 631 DE genes between DMARDs-naïve RA patients before and after ST2825 treatment. We identified 471 DE genes between LPS-stimulated RA PBMC and LPS-stimulated RA PBMC treated with ST2825. Conclusion: Our study provides comprehensive evidence supporting the potential application of the MyD88 inhibitor, ST2825, as a modulator of gene expression signtaures involved in pathogenic processes in PBMC from DMARDs-naïve RA patients. Our indepth analysis of RNA-seq data will serve as a valuable resource containing the inflammatory gene expression signatures by MyD88.

2021-11-30 | GSE189136 | GEO

Identification of microRNAs association with Rheumatoid Arthritis Synovial Fibroblasts using the Human TNF Transgenic Mouse Model

Project description:OBJECTIVE: MicroRNAs (miRNAs, miRs), a class of small non-coding RNA molecules, are posttranscriptional regulators involved in a plethora of cellular functions and have been proposed as potential therapeutic targets in various diseases, including rheumatoid arthritis (RA). In this study, we sought to discover novel miR associations in synovial fibroblasts (SFs), a key cell type mediating RA pathogenesis, by performing miR expression profiling on cells isolated from the human TNF transgenic mouse model (TghuTNF or Tg197). METHODS: miR expression in SFs isolated from 8-week-old, fully diseased TghuTNF and WT littermate control mice were determined by deep sequencing of small RNAs and the arthritic profile was established by pairwise comparisons of the two groups. qRT-PCR analysis was utilised for profile validation purposes and miR quantitation in patient SFs. Dysregulated miR target genes and pathways were predicted via bioinformatic algorithms. Synovial Fibroblasts isolated from TghuTNF mice (2 x biological replicates) and control WT littermate mice (2 x biological replicates)

2012-05-13 | E-GEOD-31667 | biostudies-arrayexpress

DNA methylation analysis of synovial fibroblasts from mice undergoing collagen-induced arthritis (CIA) treated, or not, with the the helminth-derived immunomodulator, ES-62

Project description:Aim: Synovial fibroblasts (SFs) undergo a rewiring of their DNA methylation landscape that is associated with their development of an aggressive pathogenic phenotype during Rheumatoid Arthritis (RA), both in humans and in CIA, a mouse model of this chronic inflammatory disease. The helminth-derived immunomodulator, ES-62 acts to prevent joint destruction in CIA by suppressing pathogenic SF responses. We therefore investigated whether ES-62 suppressed the changes in DNA methylation observed in SFs from CIA, relative to those from healthy, mice. Methods: The DNA methylation status of SFs from naïve (no induction of CIA), CIA and ES-62-treated mice undergoing CIA (CIA_ES-62) was compared by Reduced Representation Bilsulphite Sequencing (RRBS) analysis performed by the Active Motif service. Results: Synovial fibroblasts from naive, CIA and CIA_ES-62 mice exhibit differential genomic methylation profiles. Conclusion: ES-62 protection against joint protection in CIA is not associated with prevention of the changes in DNA methylation occurring during rewiring of naive SFs to aggressively pathogenic CIA SFs but rather, reflects generation of a distinct ES-62 phenotype of SF genomic methylation.

2021-03-01 | GSE158185 | GEO

Human fibroblast-like synoviocytes (FLSs) -derived secretome

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

Transcriptomic analysis of synovial cells derived from collagen-induced arthritis mice

Project description:The destruction of bone and cartilage results in a loss of joint functionality, critically impairing the quality of life in arthritis patients. Synovial fibroblasts (SFs) critically contribute to the pathogenesis of rheumatoid arthritis (RA) by acquiring either a pro-inflammatory or tissue-destructive phenotype. To explore the molecular mechanisms underlying the pathogenic fibroblast phenotype in arthritis, we performed single-cell RNA sequencing (scRNA-seq) on the synovial cells which were isolated from collagen-induced arthritis (CIA) mice.

2022-07-06 | GSE192504 | GEO

Identification of microRNAs association with Rheumatoid Arthritis Synovial Fibroblasts using the Human TNF Transgenic Mouse Model

2012-05-14 | GSE31667 | GEO

Repurposing of a known antipsychotic drug to target arthritogenic synovial fibroblasts

Project description:We applied quantitative mass spectrometry (MS)-based proteomics to investigate the phosphoproteome of hTNF-stimulated and Amisulpride-treated synovial fibroblasts (SFs), as part of a study aiming to find new potent orally-administered therapeutics to reverse the pathogenic expression signature of arthritogenic SFs. Phosphoproteomics analysis were done by DIA-based phosphoproteomic profiling of synovial fibroblasts. Samples consisted of hTNF-induced WT SFs. Three different time points (5’, 15’, 30’) of hTNF induction were used and compared to cells pretreated with Amisulpride for 1h before being stimulated at similar time points with hTNF (5’, 15’, 30’).

2023-04-11 | PXD035230 | Pride

miR-221/222 drive synovial fibroblast expansion and pathogenesis of TNF-mediated arthritis

Project description:MicroRNAs (miRNAs) constitute fine tuners of gene expression and are implicated in a variety of diseases spanning from inflammation to cancer. miRNA expression is deregulated in rheumatoid arthritis (RA), however, their specific role in key arthritogenic cells such as the synovial fibroblast (SF) remains elusive. We have shown in the past that the expression of the miR-221/222 cluster is upregulated in RA SFs. Here, we demonstrate that miR-221/222 activation is downstream of major inflammatory cytokines, such as TNF and IL-1β, which promote miR-221/222 expression independently. miR-221/222 expression in SFs from the huTNFtg mouse model of arthritis correlates with disease progression. Targeted transgenic overexpression of miR-221/222 in SFs of the huTNFtg mouse model led to further expansion of synovial fibroblasts and disease exacerbation. miR-221/222 overexpression altered the transcriptional profile of SFs igniting pathways involved in cell cycle progression and ECM regulation. Validated targets of miR-221/222 included p27 and p57 cell cycle inhibitors, as well as Smarca1 (a chromatin remodeling component). In contrast, complete genetic ablation of miR-221/222 in arthritic mice led to decreased proliferation of fibroblasts, reduced synovial expansion and attenuated disease. scATAC-seq data analysis revealed increased miR-221/222 gene activity in the pathogenic and activated clusters of the intermediate and lining compartment. Taken together, our results establish an SF-specific pathogenic role of the miR-221/222 cluster in arthritis and suggest that its therapeutic targeting in specific subpopulations should inform the design of novel fibroblast-targeted therapies for human disease.

2022-12-16 | GSE210887 | GEO

RNA-seq analysis of synovial fibroblasts isolated from Ets1-flox/flox and Col6a1-Cre-Ets1-flox/flox mice of serum transfer-induced arthritis (STIA)

Project description:Synovial fibroblasts critically contribute to the pathogenesis of rheumatoid arthritis (RA) by acquiring either a pro-inflammatory or tissue-destructive phenotype. To explore the molecular mechanisms underlying the tissue-destructive fibroblast phenotype in arthritis, we performed bulk RNA-sequencing analysis on the synovial fibroblasts which were isolated from Col6a1-Cre-Ets1-flox/flox (Ets1ΔFib) and Ets1-flox/flox (Ets1flox) mice.

2022-07-06 | GSE201310 | GEO

Repurposing of Amisulpride, a known antipsychotic drug, to target synovial fibroblasts activation in arthritis.

Project description:Synovial Fibroblasts (SFs) are key pathogenic drivers in arthritis and their in vivo activation by TNF is sufficient to orchestrate full arthritic pathogenesis in animal models. TNF blockade has been efficacious for a large percentage of Rheumatoid Arthritis (RA) patients, although characterized by a plethora of side effects. Novel therapeutic discoveries remain however challenging, especially in optimizing drug safety, side effects, longer-term responses, costs and administration routes. Aiming to find new potent therapeutics, we applied the L1000CDS2 search engine, in order to identify compounds that could potentially reverse the pathogenic expression signature of arthritogenic SFs, derived from the human TNF transgenic mouse model (hTNFtg). We identified a neuroleptic drug, namely Amisulpride, which was validated to reduce SFs’ inflammatory potential while decreasing the clinical score of hTNFtg polyarthritis. Notably, we found that Amisulpride did not exert its biological activities through its known targets Dopamine receptors 2 and 3 and Serotonin Receptor 7, nor through TNFTNFRI binding inhibition. By applying a click chemistry approach, novel potential targets of Amisulpride were identified, which were further validated to repress hTNFtg SFs’ inflammatory potential in vitro (Ascc3 and Sec62), while phosphoproteomics analysis revealed important fibroblast activation pathways, such as adhesion, to be altered upon treatment. Our data support that Amisulpride could provide an additive beneficial effect to patients suffering from RA and comorbid dysthymia, as it may reduce SFs pathogenicity in parallel with its antidepressive activity. Importantly, Amisulpride may also serve as a “lead” compound for the development of novel, more potent therapeutics against chronic inflammatory diseases

2023-04-06 | PXD036283 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data