scholarly journals The Mechanisms Underlying Chronic Inflammation in Rheumatoid Arthritis from the Perspective of the Epigenetic Landscape

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Yasuto Araki ◽  
Toshihide Mimura
Keyword(s):  
Rheumatoid Arthritis ◽  
Joint Destruction ◽  
Synovial Fibroblasts ◽  
Cell Types ◽  
Epigenetic Mechanisms ◽  
Synovial Hyperplasia ◽  
Genetic And Environmental Factors ◽  
Inflammatory Autoimmune Disease ◽  
Fibroblast Like Synoviocytes

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that is characterized by synovial hyperplasia and progressive joint destruction. The activation of RA synovial fibroblasts (SFs), also called fibroblast-like synoviocytes (FLS), contributes significantly to perpetuation of the disease. Genetic and environmental factors have been reported to be involved in the etiology of RA but are insufficient to explain it. In recent years, accumulating results have shown the potential role of epigenetic mechanisms, including histone modifications, DNA methylation, and microRNAs, in the development of RA. Epigenetic mechanisms regulate chromatin state and gene transcription without any change in DNA sequence, resulting in the alteration of phenotypes in several cell types, especially RASFs. Epigenetic changes possibly provide RASFs with an activated phenotype. In this paper, we review the roles of epigenetic mechanisms relevant for the progression of RA.

The Role of Synovial Fibroblasts in Mediating Joint Destruction in Rheumatoid Arthritis

2005 ◽  
Vol 11 (5) ◽  
pp. 563-568 ◽  
Author(s):  
Ingmar Meinecke ◽  
Edita Rutkauskaite ◽  
Steffen Gay ◽  
Thomas Pap
Keyword(s):  
Rheumatoid Arthritis ◽  
Joint Destruction ◽  
Synovial Fibroblasts

scholarly journals DNA Methylation as a Future Therapeutic and Diagnostic Target in Rheumatoid Arthritis

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 953 ◽  
Author(s):  
Marzena Ciechomska ◽  
Leszek Roszkowski ◽  
Wlodzimierz Maslinski
Keyword(s):  
Rheumatoid Arthritis ◽  
Dna Methylation ◽  
Joint Destruction ◽  
Synovial Fibroblasts ◽  
Genetic Mutation ◽  
Unknown Etiology ◽  
Non Invasive ◽  
Fibroblast Like Synoviocytes

Rheumatoid arthritis (RA) is a long-term autoimmune disease of unknown etiology that leads to progressive joint destruction and ultimately to disability. RA affects as much as 1% of the population worldwide. To date, RA is not a curable disease, and the mechanisms responsible for RA development have not yet been well understood. The development of more effective treatments and improvements in the early diagnosis of RA is direly needed to increase patients’ functional capacity and their quality of life. As opposed to genetic mutation, epigenetic changes, such as DNA methylation, are reversible, making them good therapeutic candidates, modulating the immune response or aggressive synovial fibroblasts (FLS—fibroblast-like synoviocytes) activity when it is necessary. It has been suggested that DNA methylation might contribute to RA development, however, with insufficient and conflicting results. Besides, recent studies have shown that circulating cell-free methylated DNA (ccfDNA) in blood offers a very convenient, non-invasive, and repeatable “liquid biopsy”, thus providing a reliable template for assessing molecular markers of various diseases, including RA. Thus, epigenetic therapies controlling autoimmunity and systemic inflammation may find wider implications for the diagnosis and management of RA. In this review, we highlight current challenges associated with the treatment of RA and other autoimmune diseases and discuss how targeting DNA methylation may improve diagnostic, prognostic, and therapeutic approaches.

CXCL10 and TRAIL Are Upregulated by TXNDC5 in Rheumatoid Arthritis Fibroblast-like Synoviocytes

2017 ◽  
Vol 45 (3) ◽  
pp. 335-340 ◽  
Author(s):  
Bing Xu ◽  
Jian Li ◽  
Changsun Wu ◽  
Chunyan Liu ◽  
Xinfeng Yan ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Synovial Fibroblasts ◽  
And Migration ◽  
Interfering Rna ◽  
Synovial Membranes ◽  
Necrosis Factor ◽  
Fibroblast Like Synoviocytes

Objective.Thioredoxin domain containing 5 (TXNDC5) is highly expressed in synovial membranes of rheumatoid arthritis (RA). Our study aimed to investigate the pathogenic role of TXNDC5 in RA.Methods.PCR arrays, CCK-8 assays, flow cytometry, and transwell migration assays were used to analyze cultured rheumatoid arthritis synovial fibroblasts (RASF).Results.Increased CXCL10 and tumor necrosis factor-related apoptosis-inducing ligand levels were detected in RASF transfected with anti-TXNDC5 small interfering RNA (siRNA), and decreased expression was detected in RASF transfected with TXNDC5-expressing plasmids. Significantly attenuated RASF proliferation and migration, and increased RASF apoptosis, were observed in the siRNA-transfected RASF.Conclusion.Downregulation of TXNDC5 could contribute to RASF antiangiogenic and proapoptotic features through the suppression of CXCL10 and TRAIL (tumor necrosis factor-related apoptosis-inducing ligand).

scholarly journals Dysregulation of lncRNAs in Rheumatoid Arthritis: Biomarkers, Pathogenesis and Potential Therapeutic Targets

2021 ◽  
Vol 12 ◽  
Author(s):  
Chenggui Miao ◽  
Liangliang Bai ◽  
Yaru Yang ◽  
Jinling Huang
Keyword(s):  
Rheumatoid Arthritis ◽  
Epigenetic Modification ◽  
Joint Destruction ◽  
Research Progress ◽  
Unknown Etiology ◽  
Signal Pathways ◽  
Cartilage Erosion ◽  
Chronic Autoimmune Disease ◽  
Fibroblast Like Synoviocytes

Rheumatoid arthritis (RA) is a chronic autoimmune disease of unknown etiology, mainly manifested by persistent abnormal proliferation of fibroblast-like synoviocytes (FLSs), inflammation, synovial hyperplasia and cartilage erosion, accompanied by joint swelling and joint destruction. Abnormal expression or function of long noncoding RNAs (lncRNAs) are closely related to human diseases, including cancers, mental diseases, autoimmune diseases and others. The abnormal sequence and spatial structure of lncRNAs, the disorder expression and the abnormal interaction with the binding protein will lead to the change of gene expression in the way of epigenetic modification. Increasing evidence demonstrated that lncRNAs were involved in the activation of FLSs, which played a key role in the pathogenesis of RA. In this review, the research progress of lncRNAs in the pathogenesis of RA was systematically summarized, including the role of lncRNAs in the diagnosis of RA, the regulatory mechanism of lncRNAs in the pathogenesis of RA, and the intervention role of lncRNAs in the treatment of RA. Furthermore, the activated signal pathways, the role of DNA methylation and other mechanism have also been overview in this review.

scholarly journals Arthritis and the role of endogenous glucocorticoids

Bone Research ◽  
2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Eugenie Macfarlane ◽  
Markus J. Seibel ◽  
Hong Zhou
Keyword(s):  
Rheumatoid Arthritis ◽  
Joint Destruction ◽  
Degenerative Joint Disease ◽  
Joint Disease ◽  
Current Evidence ◽  
Inflammatory Microenvironment ◽  
Glucocorticoid Signaling ◽  
Anti Inflammatory ◽  
Fibroblast Like Synoviocytes

Abstract Rheumatoid arthritis and osteoarthritis, the most common forms of arthritis, are chronic, painful, and disabling conditions. Although both diseases differ in etiology, they manifest in progressive joint destruction characterized by pathological changes in the articular cartilage, bone, and synovium. While the potent anti-inflammatory properties of therapeutic (i.e., exogenous) glucocorticoids have been heavily researched and are widely used in clinical practice, the role of endogenous glucocorticoids in arthritis susceptibility and disease progression remains poorly understood. Current evidence from mouse models suggests that local endogenous glucocorticoid signaling is upregulated by the pro-inflammatory microenvironment in rheumatoid arthritis and by aging-related mechanisms in osteoarthritis. Furthermore, these models indicate that endogenous glucocorticoid signaling in macrophages, mast cells, and chondrocytes has anti-inflammatory effects, while signaling in fibroblast-like synoviocytes, myocytes, osteoblasts, and osteocytes has pro-inflammatory actions in rheumatoid arthritis. Conversely, in osteoarthritis, endogenous glucocorticoid signaling in both osteoblasts and chondrocytes has destructive actions. Together these studies provide insights into the role of endogenous glucocorticoids in the pathogenesis of both inflammatory and degenerative joint disease.

Mechanisms of bone and cartilage destruction

2020 ◽  
pp. 85-94
Author(s):  
Ulrike Harre ◽  
Georg Schett
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Cytokines ◽  
Structural Damage ◽  
Current Knowledge ◽  
Joint Destruction ◽  
Cell Types ◽  
Significant Burden ◽  
Repair Mechanisms ◽  
And Cartilage ◽  
Fibroblast Like Synoviocytes

Structural damage of cartilage and bone tissue is a hallmark of rheumatoid arthritis (RA). The resulting joint destruction constitutes one of the major disease consequences for patients and creates a significant burden for the society. The main cells executing bone and cartilage degradation are osteoclasts and fibroblast-like synoviocytes, respectively. The function of both cell types is influenced by the immune system. In past decades, research has identified several mediators of structural damage, ranging from infiltrating immune cells and inflammatory cytokines to autoantibodies. These factors result in an inflammatory milieu in the affected joints, which leads to an increased development and function of osteoclasts and the transformation of fibroblast-like synoviocytes towards a highly migratory and destructive phenotype. In addition, repair mechanisms mediated by osteoblasts and chondrocytes are strongly impaired by the presence of pro-inflammatory cytokines. This article will review the current knowledge on the mechanisms of destruction of bone and cartilage in rheumatoid arthritis.

scholarly journals Loss of the WNT9a ligand aggravates the rheumatoid arthritis-like symptoms in hTNF transgenic mice

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Stefan Teufel ◽  
Petra Köckemann ◽  
Christine Fabritius ◽  
Lena I. Wolff ◽  
Jessica Bertrand ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Soft Tissue ◽  
Mouse Model ◽  
Wnt Signaling ◽  
Joint Destruction ◽  
Wnt Signaling Pathway ◽  
Synovial Fibroblasts ◽  
Canonical Wnt

AbstractAgonists and antagonists of the canonical Wnt signaling pathway are modulators of pathological aspects of rheumatoid arthritis (RA). Their activity is primarily modifying bone loss and bone formation, as shown in animal models of RA. More recently, modulation of Wnt signaling by the antagonist Sclerostin has also been shown to influence soft-tissue-associated inflammatory aspects of the disease pointing towards a role of Wnt signaling in soft-tissue inflammation as well. Yet, nothing is known experimentally about the role of Wnt ligands in RA. Here we provide evidence that altering Wnt signaling at the level of a ligand affects all aspects of the rheumatoid arthritic disease. WNT9a levels are increased in the pannus tissue of RA patients, and stimulation of synovial fibroblasts (SFB) with tumor necrosis factor (TNF) leads to increased transcription of Wnt9a. Loss of Wnt9a in a chronic TNF-dependent RA mouse model results in an aggravation of disease progression with enhanced pannus formation and joint destruction. Yet, loss of its activity in the acute K/BxN serum-transfer induced arthritis (STIA) mouse model, which is independent of TNF signaling, has no effect on disease severity or progression. Thus, suggesting a specific role for WNT9a in TNF-triggered RA. In synovial fibroblasts, WNT9a can activate the canonical Wnt/β-catenin pathway, but it can also activate P38- and downregulate NFκB signaling. Based on in vitro data, we propose that loss of Wnt9a creates a slight proinflammatory and procatabolic environment that boosts the TNF-mediated inflammatory response.

The role of histone deacetylases in rheumatoid arthritis fibroblast-like synoviocytes

2013 ◽  
Vol 41 (3) ◽  
pp. 783-788 ◽  
Author(s):  
Sarah Hawtree ◽  
Munitta Muthana ◽  
Anthony G. Wilson
Keyword(s):  
Rheumatoid Arthritis ◽  
Transcriptional Repression ◽  
Histone Deacetylases ◽  
Regulation Of Gene Expression ◽  
Hdac Inhibitors ◽  
Cell Types ◽  
Epigenetic Mark ◽  
Aggressive Phenotype ◽  
Fibroblast Like Synoviocytes

RA (rheumatoid arthritis) is an inflammatory disease of synovial joints affecting approximately 1% of the population. One of the main cell types involved in damage to RA joint tissue is the FLSs (fibroblast-like synoviocytes). These have a semi-transformed, auto-aggressive phenotype typified by loss of contact inhibition, reduced apoptosis and the production of matrix-degrading enzymes. The mechanisms involved in the development of this phenotype are unclear; however, increasing evidence implicates alterations in the epigenetic regulation of gene expression. Reduced acetylation of amino acids in the tails of histone proteins is an epigenetic mark associated with transcriptional repression and is controlled by the HDAC (histone deacetylase) enzyme family. To date, evidence has implicated HDACs in the auto-aggressive phenotype of FLSs, and administration of HDAC inhibitors to both animal models of RA and individuals with juvenile arthritis has shown efficacy in attenuating inflammation and tissue damage. This highlights a role for HDACs in disease pathogenesis and, more importantly, that HDACs are potential novel therapeutic targets.

scholarly journals MiR-199a-3p inhibits proliferation and induces apoptosis in rheumatoid arthritis fibroblast-like synoviocytes via suppressing retinoblastoma 1

2018 ◽  
Vol 38 (6) ◽  
Author(s):  
Yufan Wangyang ◽  
Linhong Yi ◽  
Tao Wang ◽  
Yanbo Feng ◽  
Guangwang Liu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Cell Proliferation ◽  
Ectopic Expression ◽  
Cell Types ◽  
Rb1 Gene ◽  
Resistant Variant ◽  
Direct Target ◽  
Induced Apoptosis ◽  
Fibroblast Like Synoviocytes

Background Fibroblast-like synoviocytes (FLSs) that line the intimal synovium play a crucial role in the pathogenesis of rheumatoid arthritis (RA). miR-199a-3p is a highly conserved miRNA that has been shown to regulate a variety of growth behaviors in diverse cell types. However, the role of miR-199a-3p in RA-FLS is still unknown. Methods Here, we presented the first experimental evidence showing that miR-199a-3p was a critical regulator of RA-FLS function. Results miR-199a-3p expression was significantly reduced in RA-FLS compared with normal FLS. Ectopic expression of miR-199a-3p significantly inhibited RA-FLS proliferation and induced apoptosis, which was demonstrated by an increase in caspase-3 activity and Bax/Bcl-2 ratio. Our bioinformatics analysis identified Retinoblastoma 1 (RB1) gene to be a direct target of miR-199a-3p. In RA-FLS, miR-199a-3p directly targetted the 3′-UTR of RB1 mRNA and suppressed endogenous RB1 expression, whereas miR-199a-3p-resistant variant of RB1 was not affected. Silencing RB1 decreased cell proliferation and promoted apoptosis in RA-FLS, an effect comparable with miR-199a-3p overexpression. Enforced expression of RB1 partially restored cell proliferation and attenuated apoptosis in miR-199a-3p-overexpressing RA-FLSs. Conclusion In summary, miR-199a-3p is down-regulated in RA-FLS, and miR-199a-3p inhibits proliferation and induces apoptosis in RA-FLS, partially via targetting RB1. The miR-199a-3p/RB1 pathway may represent a new therapeutic target for RA.

scholarly journals SFRP5 Enhances Wnt5a Induced-Inflammation in Rheumatoid Arthritis Fibroblast-Like Synoviocytes

2021 ◽  
Vol 12 ◽  
Author(s):  
Dorra Elhaj Mahmoud ◽  
Wajih Kaabachi ◽  
Nadia Sassi ◽  
Amel Mokhtar ◽  
Myriam Moalla ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Joint Destruction ◽  
Pannus Formation ◽  
Time Points ◽  
Protein Levels ◽  
Inflammatory Molecules ◽  
Fibroblast Like Synoviocytes ◽  
Inflammatory Effect

BackgroundTissue derived fibroblast-like synoviocytes (td-FLS) are key actors in pannus formation and contribute to joint destruction and inflammation during rheumatoid arthritis (RA). Several members of the Wnt family, including Wnt5a, may contribute to RA td-FLS activation and can potentially serve as therapeutic targets.ObjectiveThe present work aimed to investigate the expression of Wnt5a signaling elements in RA td-FLS and their potential precursors (fluid derived (fd) FLS and fibrocytes). We also studied the role of Wnt5a in RA td-FLS pro-inflammatory activity and whether the inhibitor SFRP5 could restore Wnt5a-induced synovial dysfunction in vitro.Materials and MethodsThe levels of Wnt5a, SFRP5, Wnt5a receptors/coreceptors and Wnt5a pro-inflammatory targets were determined in cultured RA td-FLS, fd-FLS and fibrocytes using qPCR under basal conditions. The expression of pro-inflammatory molecules was assessed after RA td-FLS stimulation with Wnt5a and SFRP5 at different time points.ResultsOur data showed that td-FLS, fd-FLS and fibrocytes from patients with RA expressed similar levels of Wnt5a and a set of Wnt5a receptors/coreceptors. We also demonstrated that Wnt5a stimulated the expression of the pro-inflammatory targets, especially IL1β, IL8 and IL6 in RA td-FLS. Wnt5a-induced inflammation was enhanced in the presence of SFRP5. Furthermore, Wnt5a alone and in conjunction with SFRP5 inhibited the gene expression of TCF4 and the protein levels of the canonical coreceptor LRP5.ConclusionWnt5a pro-inflammatory effect is not inhibited but enhanced by SFRP5 in RA td-FLS. This research highlights the importance of carefully evaluating changes in Wnt5a response in the presence of SFRP5.

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