BRD3 regulates the inflammatory and stress response in rheu-matoid arthritis synovial fibroblasts
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ABSTRACT:
PROVIDER: PRJNA1036660 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26704600.fastq.gz | Fastqsanger.gz | |||
| SRR26704601.fastq.gz | Fastqsanger.gz | |||
| SRR26704602.fastq.gz | Fastqsanger.gz | |||
| SRR26704603.fastq.gz | Fastqsanger.gz | |||
| SRR26704592.fastq.gz | Fastqsanger.gz |
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Project description:Individual functions of members of the bromodomain (BRD) and extra-terminal (BET) protein family underlying the anti-inflammatory effects of BET inhibitors in rheumatoid arthritis (RA) are incompletely understood. Here we aimed to analyze regulatory functions of BRD3, an under-studied member of the BET protein family, in RA synovial fibroblasts (FLS). BRD3 was silenced in FLS prior to stimulation with TNF. Alternatively, FLS were treated with I-BET. Transcriptomes were analyzed by RNA sequencing (RNAseq), followed by pathway enrichment analysis. We confirmed results for selective target genes by Real-time PCR, ELISA and Western blotting. BRD3 regulates the expression of several cytokines and chemokines in FLS, and positively correlates with inflammatory scores in the RA synovium. In addition, RNAseq pointed to a profound role of BRD3 in regulating FLS proliferation, metabolic adaption, and response to stress, including oxidative stress, and autophagy. BRD3 acts as an upstream regu-latory factor that integrates the response to inflammatory stimuli and stress conditions in FLS and executes many functions of BET proteins that have previously identified using pan-BET inhibitors.
2023-11-30 | GSE247226 | GEO
Project description:Inflammatory arthritis is associated with bone loss and fractures due to abnormal bone remodelling. Bone remodelling is 'uncoupled' with bone resorption increased and bone formation suppressed. These changes resemble those seen in patients treated with therapeutic glucocorticoids, and in both of these situations, altered wnt signalling is implicated. Recent studies have highlighted the importance of the synovial fibroblast in mediating abnormal bone remodelling during inflammation. The wnt antagonist dickkopf-1 (DKK1) is secreted by synovial fibroblasts in response to inflammation, and this protein has been proposed to be a master regulator of bone remodelling in inflammatory arthritis. Here we show that DKK1 expression by primary human synovial fibroblasts is more potently regulated by glucocorticoids than pro-inflammatory cytokines. Glucocorticoids, but not TNF-alpha, regulated expression of multiple wnt agonists and antagonists in favour of inhibition of wnt signalling. In vitro TNF-alpha and IL1-beta indirectly regulate DKK1 production through increased expression of the glucocorticoid activating enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). These results demonstrate that the links between synovial inflammation, altered wnt signalling and bone remodelling may not be direct but are dependent on local activation of endogenous glucocorticoids. Human fibroblast-like synoviocytes isolated from patients with rheumatoid arthritis treated with either vehicle, TNF or dexamethasone (dex). Gene arrays for control, TNF and dexamethasone treatments were performed on three separate synovial fibroblast cell lines isolated from three rheumatoid arthritis patients. All fold changes displayed are the combined results of the three separate fibroblast lines.
2012-04-24 | E-GEOD-37520 | biostudies-arrayexpress
Project description:The role of synovial tissue fibroblasts and macrophages interactions in driving chronic inflammation and resolution of arthritis is unknown. In this project, we used bulk RNAseq to investigate the impact of different phenotypes of macrophages on activation of synovial fibroblasts.
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Project description:Inflammatory tissues are characterized by low oxigen concentrations (hypoxia). These conditions are very different from that usually present in tissue cultures where transcriptomic profiles of human fibroblasts from inflammatory tissues have been previously analysed. The aim of this study was to characterize the changes on gene expression induced by hypoxia in human synovial fibroblasts. We used microarray expression profiling in paired normoxic and hypoxic cultures of healthy and rheumatoid arthritis (RA) synovial fibroblasts (HSF and RASF). Hypoxia induces significant changes on the expression of large groups of genes in both HSF and RASF. The hypoxic and normoxic profiles are also different between both groups. These data demonstrate that hypoxia induces significant changes on gene expression in HSF and RASF and identify differences between RASF and HSF. Synovial fibroblasts obtained from 6 patients with rheumatoid arthritis (RASF) and 6 sex and age matched adult healthy donors (HSF) were used. SF cultures were incubated for 22 hours under normoxic or hypoxic (0.5% O2) conditions. Nine experiments per group were performed, single experiments with three SF lines, and duplicated in other three lines per group. All 18 normoxia-hypoxia experiments (36 microarray data) were used for paired analysis of the changes induced by hypoxia in HSF or RASF.
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Project description:Transcriptional profiling of human rheumatoid arthritis synovial fibroblasts comparing control cells treated with BSA with cells treated with Tenascin-C.
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Project description:Inflammatory arthritis is associated with bone loss and fractures due to abnormal bone remodelling. Bone remodelling is 'uncoupled' with bone resorption increased and bone formation suppressed. These changes resemble those seen in patients treated with therapeutic glucocorticoids, and in both of these situations, altered wnt signalling is implicated. Recent studies have highlighted the importance of the synovial fibroblast in mediating abnormal bone remodelling during inflammation. The wnt antagonist dickkopf-1 (DKK1) is secreted by synovial fibroblasts in response to inflammation, and this protein has been proposed to be a master regulator of bone remodelling in inflammatory arthritis. Here we show that DKK1 expression by primary human synovial fibroblasts is more potently regulated by glucocorticoids than pro-inflammatory cytokines. Glucocorticoids, but not TNF-alpha, regulated expression of multiple wnt agonists and antagonists in favour of inhibition of wnt signalling. In vitro TNF-alpha and IL1-beta indirectly regulate DKK1 production through increased expression of the glucocorticoid activating enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). These results demonstrate that the links between synovial inflammation, altered wnt signalling and bone remodelling may not be direct but are dependent on local activation of endogenous glucocorticoids.
2012-04-24 | GSE37520 | GEO
Project description:Inflammatory tissues are characterized by low oxigen concentrations (hypoxia). These conditions are very different from that usually present in tissue cultures where transcriptomic profiles of human fibroblasts from inflammatory tissues have been previously analysed. The aim of this study was to characterize the changes on gene expression induced by hypoxia in human synovial fibroblasts. We used microarray expression profiling in paired normoxic and hypoxic cultures of healthy and rheumatoid arthritis (RA) synovial fibroblasts (HSF and RASF). Hypoxia induces significant changes on the expression of large groups of genes in both HSF and RASF. The hypoxic and normoxic profiles are also different between both groups. These data demonstrate that hypoxia induces significant changes on gene expression in HSF and RASF and identify differences between RASF and HSF.
2010-12-10 | GSE21959 | GEO
Project description:Macrophages have plasticity to adapt microenvironment. In joint tissue, synovial macrophages (SM) and synovial fibroblasts (SF) are maintained in the homeostasis. In Rheumatoid arthritis, crosstalk between SM and SF via inflammatory response induce abnormal activation in respective cells and contribute to disease progression. However, the activation mechanisms in SM which are encouraged by SF are largely unclear. Here, we demonstrated metabolic reprogramming and immunological activation in SM by secretary stimulations from SF using primary culture synovial cell derived from arthritis model mice. To analyze interaction between SM and SF, primary culture of murine synovial cells was performed, respectively. RNA-seq analysis showed SF express abundant secretion-related gene. Thus, we investigated whether conditioned medium from SF (SF-CM) affects biological activity in SM. As the results, SF-CM condition induced both glycolysis and mitochondrial respiration to SM with increased uptake of glucose and glutamine at least, accompanied with cell survival. In addition, several inflammation markers were also upregulated in SM by SF-CM condition. Taken together, these results suggest that metabolic reprogramming were induced in SM by secretory stimulations from SF, followed by activated inflammatory response and long-live. These indicate that such phenotypes of SM may contribute to chronic inflammation in Rheumatoid arthritis
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