Fibroblast pathology in inflammatory joint disease

Marsh, Lucy-Jayne; Kemble, Samuel; Nisa, Patricia Reis; Singh, Rajvir; Croft, Adam P.

doi:10.1111/imr.12986

Cited by 33 publications

(25 citation statements)

References 200 publications

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“…Fibroblasts are the main component of the inner wall of the joint cavity called the synovium. During joint inflammation, fibroblasts promote the recruitment and retention of inflammatory cells by producing inflammatory mediators at pathogenic levels, thereby contributing to disease pathology [ 25 ]. The MH7A synovial fibroblast cell line used in this experiment is a chemically treated cell line extracted from the synovium of a female RA patient using SV40 T antigen.…”

Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: Dehydroevodiamine suppresses inflammatory responses in adjuvant-induced arthritis rats and human fibroblast-like synoviocytes

Dai

Sheng

et al. 2021

Bioengineered

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Dehydroevodiamine (DHE) is an effective natural active substance extracted from Euodiae Fructus , which is a widely used herbal drug in traditional Chinese medicine. The focus of this study was to test the possibility of using DHE in the treatment of rheumatoid arthritis (RA) diseases. A rat model of adjuvant-induced arthritis (AIA) was generated using Complete Freund’s Adjuvant (CFA). Body weight changes, arthritis scores, ankle pathology, tumor necrosis factor-alpha (TNF-α), interleukin-1β(IL-1β), interleukin-6 (IL-6), and interleukin-17 (IL-17) secretion, as well as matrix metalloproteinase (MMP) expression in joint tissue, were measured as indicators of viability of DHE medicated AIA rats. Human fibroblast-like synoviocytes (MH7A cells) were connected to check these impacts. The results confirmed that DHE administration had an excellent therapeutic impact on the AIA rat model, substantially relieving joint swelling, inhibiting synovial pannus hyperplasia, and decreasing joint scores. In addition, the serum enzyme-linked immunosorbent assay (ELISA) showed that DHE treatment reduced the expression of pro-inflammatory factors in AIA rats. The immunohistochemical results showed that DHE treatment could reduce the synthesis of MMPs such as matrix metalloproteinase-1(MMP-1) and matrix metalloproteinase-3 (MMP-3) in the ankle tissue of AIA rats. In vitro, DHE inhibited cell proliferation, mRNA transcription, protein synthesis of proinflammatory factors such as IL-1βand IL-6, and matrix metalloproteinases such as MMP-1 and MMP-3. Furthermore, DHE inhibited the phosphorylation levels of p38, JNK, and ERK proteins in TNF-α-treated MH7A cells.This work assessed the effect of DHE in AIA rats and revealed its mechanism in vitro.

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Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: Dehydroevodiamine suppresses inflammatory responses in adjuvant-induced arthritis rats and human fibroblast-like synoviocytes

Dai

Sheng

et al. 2021

Bioengineered

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“…Because recent studies using single-cell RNA-seq (scRNA-seq) on RA synovium identified specific fibroblast subsets with critical roles in RA pathogenesis 13 , 14 , 16 , 29 , we applied modular analysis based on scRNA-seq fibroblast subsets 14 and orthogonal validation by multiplex immunofluorescence, and identified an association between DKK3 + fibroblasts and refractoriness. DKK3 encodes Dickkopf3, a negative regulator of beta-catenin that has been shown to promote aggressive behaviour in cancer-associated fibroblasts 30 , although the exact function of DKK3 + fibroblasts in RA remains to be established 31 . Furthermore, DSP revealed specific upregulation of genes in the sublining of refractory patients encoding for the fibroblast marker FAP, which has been linked with RA pathogenesis 16 , while other markers consistently modulated across all regions included CCL13 encoding for the monocyte-attracting chemokine MCP-4, which has been shown to activate synovial fibroblasts 32 .…”

Section: Discussionmentioning

confidence: 99%

Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial

Rivellese

Surace

Goldmann

et al. 2022

Nat Med

137

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Patients with rheumatoid arthritis (RA) receive highly targeted biologic therapies without previous knowledge of target expression levels in the diseased tissue. Approximately 40% of patients do not respond to individual biologic therapies and 5–20% are refractory to all. In a biopsy-based, precision-medicine, randomized clinical trial in RA (R4RA; n = 164), patients with low/absent synovial B cell molecular signature had a lower response to rituximab (anti-CD20 monoclonal antibody) compared with that to tocilizumab (anti-IL6R monoclonal antibody) although the exact mechanisms of response/nonresponse remain to be established. Here, in-depth histological/molecular analyses of R4RA synovial biopsies identify humoral immune response gene signatures associated with response to rituximab and tocilizumab, and a stromal/fibroblast signature in patients refractory to all medications. Post-treatment changes in synovial gene expression and cell infiltration highlighted divergent effects of rituximab and tocilizumab relating to differing response/nonresponse mechanisms. Using ten-by-tenfold nested cross-validation, we developed machine learning algorithms predictive of response to rituximab (area under the curve (AUC) = 0.74), tocilizumab (AUC = 0.68) and, notably, multidrug resistance (AUC = 0.69). This study supports the notion that disease endotypes, driven by diverse molecular pathology pathways in the diseased tissue, determine diverse clinical and treatment–response phenotypes. It also highlights the importance of integration of molecular pathology signatures into clinical algorithms to optimize the future use of existing medications and inform the development of new drugs for refractory patients.

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“…Remodeling the epigenome is likely underlying these stable pathologic changes in SF gene expression and function (38,39). For instance, DNA methylation patterns in SFs from RA patients are very distinct from those in osteoarthritis and SFs from non-inflamed individuals (40).…”

Section: Discussionmentioning

confidence: 99%

Reset of Inflammatory Priming of Joint Tissue and Reduction of the Severity of Arthritis Flares by Bromodomain Inhibition

Friščić

Reinwald

Böttcher

et al. 2023

Arthritis & Rheumatology

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OBJECTIVE: We have recently shown that priming of synovial fibroblasts (SFs) drives arthritis flares. Pathogenic priming of SFs is essentially mediated by epigenetic reprogramming. Bromodomain and extra-terminal motif (BET) proteins translate epigenetic changes into transcription. Here we used a BET inhibitor to target inflammatory tissue priming and reduce flare severity in experimental arthritis. METHODS: BALB/c mice were treated intraperitoneally or locally into the paw with I-BET151, which blocks interaction of BET proteins with acetylated histones. Effect of I-BET151 on acute arthritis and/or inflammatory tissue priming was assessed in a model of repeated injections of monosodium urate crystals or zymosan into the paw. I-BET151 was given either from before arthritis induction, at peak inflammation, or after healing of the first arthritis bout. Transcriptomic (RNA-Seq), epigenomic (ATAC-Seq) and functional analysis (invasion, cytokine production, migration, senescence, metabolic flux) was performed on murine and human SFs treated with I-BET151 in vitro or in vivo. RESULTS: Systemic I-BET151 administration did not affect acute inflammation but abolished inflammatory tissue priming and diminished flare severity in both preventive and therapeutic treatment settings. I-BET151 was also effective when applied locally in the joint. BET inhibition also inhibited osteoclast differentiation, while macrophage activation in the joint was not affected. Flare reduction after BET inhibition was mediated, at least in part, by rolling back the primed transcriptional, metabolic and pathogenic phenotype of SFs. CONCLUSION: Inflammatory tissue priming is dependent on transcriptional regulation by BET proteins, which makes them promising therapeutic targets for preventing arthritis flares in previously affected joints.

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Fibroblast pathology in inflammatory joint disease

Cited by 33 publications

References 200 publications

RETRACTED ARTICLE: Dehydroevodiamine suppresses inflammatory responses in adjuvant-induced arthritis rats and human fibroblast-like synoviocytes

RETRACTED ARTICLE: Dehydroevodiamine suppresses inflammatory responses in adjuvant-induced arthritis rats and human fibroblast-like synoviocytes

Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial

Reset of Inflammatory Priming of Joint Tissue and Reduction of the Severity of Arthritis Flares by Bromodomain Inhibition

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