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

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

Frontiers in Pharmacology ◽

10.3389/fphar.2021.652751 ◽

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.

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Arthritis and the role of endogenous glucocorticoids

Bone Research ◽

10.1038/s41413-020-00112-2 ◽

2020 ◽

Vol 8 (1) ◽

Cited By ~ 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.

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

Cell Death and Disease ◽

10.1038/s41419-021-03786-6 ◽

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.

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TSP1 is the essential domain of SEMA5A involved in pannus formation in rheumatoid arthritis

Rheumatology ◽

10.1093/rheumatology/keab133 ◽

2021 ◽

Author(s):

Chipeng Xiao ◽

Chen Lv ◽

Siyuan Sun ◽

Heping Zhao ◽

Hanzhi Ling ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Transcriptome Sequencing ◽

Bioinformatics Analysis ◽

Tube Formation ◽

Pannus Formation ◽

Joint Injury ◽

Formation Experiment ◽

Essential Domain ◽

Fibroblast Like Synoviocytes

Abstract Objective In this study, we explored the effect of semaphorin5A (SEMA5A) on rheumatoid arthritis (RA) pathogenesis and its specific TSP1 domain on pannus formation. Methods The expression of SEMA5A was detected in synovium, fibroblast-like synoviocytes (FLS) and synovial fluid of RA patients and healthy controls (HCs) by q-PCR, IHC, WB and ELISA. SEMA5A-mAb intervention was performed to appraise the severity of joints in CIA model. Transcriptome sequencing and bioinformatics analysis in SEMA5A transfected FLS from HCs were performed to screen differentially expressed genes after SEMA5A overexpression. MTT assay in RA-FLS, chicken embryo allantoic membrane experiment and tube formation experiment were used to clarify the influence of SEMA5A on cell proliferation and angiogenesis. Furthermore, rescue experiment verified the function of TSP1 domain of SEMA5A in the progress of RA with Sema5a-/- CIA mice. Results The expression of SEMA5A increased in RA compared with HCs. Simultaneously, SEMA5A-mAb significantly attenuated joint injury and inflammatory response in CIA models. Besides, transcriptome sequencing and angiogenesis-related experiments verified the ability of SEMA5A to promote FLS proliferation and angiogenesis. Moreover, TSP1 was proved as an essential domain in SEMA5A-inducing angiogenesis in vitro. Additionally, rescue of TSP1-deleted SEMA5A failed to deteriorate the severity of arthritis in CIA model constructed with Sema5a -/- mice. Conclusions In summary, up-regulation of SEMA5A was firstly confirmed in pathological lesion of RA patients. Furthermore, the treatment of SEMA5A-mAb attenuated the progress of RA in CIA model. Moreover, TSP1 was indicated as the key domain of SEMA5A to promote pannus formation in RA.

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CD109 regulates the inflammatory response and is required for the pathogenesis of rheumatoid arthritis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2019-215473 ◽

2019 ◽

Vol 78 (12) ◽

pp. 1632-1641 ◽

Cited By ~ 4

Author(s):

Guanhua Song ◽

Tingting Feng ◽

Ru Zhao ◽

Qiqi Lu ◽

Yutao Diao ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Inflammatory Response ◽

Osteoclast Differentiation ◽

Small Interfering Rnas ◽

Inflammatory Stimuli ◽

Synovial Tissues ◽

Factor Α ◽

Fibroblast Like Synoviocytes

ObjectiveThe aim of this study was to investigate the role of CD109 in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLSs) and to evaluate its potential as a therapeutic target.MethodsCD109 expression was examined in synovial tissues and FLSs from RA patients and collagen-induced arthritis (CIA) model mice. CD109-deficient mice were developed to evaluate the severity of CIA. Small interfering RNAs and a neutralising antibody against CD109 (anti-CD109) were designed for functional or treatment studies in RA FLSs and CIA.ResultsCD109 was found to be abundantly expressed in the synovial tissues from RA patients and CIA mice. CD109 expression in RA FLSs was upregulated by inflammatory stimuli, such as interleukin-1β and tumour necrosis factor-α. Silencing of CD109 or anti-CD109 treatment reduced proinflammatory factor production, cell migration, invasion, chemoattractive potential and osteoclast differentiation, thereby reducing the deleterious inflammatory response of RA FLSs in vitro. Mice lacking CD109 were protected against arthritis in the CIA model. Anti-CD109 treatment prevented the onset and ameliorated the severity of CIA lesions.ConclusionOur study uncovers an antiarthritic role for CD109 and suggests that CD109 inhibition might serve as a promising novel therapeutic strategy for RA.

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The Role of miR-382-5p in Rheumatoid Arthritis: An In Vitro Study with Fibroblast-Like Synoviocytes

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2020.2227 ◽

2020 ◽

Vol 10 (2) ◽

pp. 169-175

Author(s):

Deqian Meng ◽

Wenyou Pan ◽

Ju Li

Keyword(s):

Rheumatoid Arthritis ◽

In Vitro Study ◽

Underlying Mechanism ◽

High Morbidity ◽

Systemic Autoimmunity ◽

Autoimmune Inflammatory Disease ◽

Proliferation And Invasion ◽

Fibroblast Like Synoviocytes

Rheumatoid arthritis (RA) is a common autoimmune inflammatory disease with high morbidity. MiR-382-5p may be associated with progression from systemic autoimmunity to RA inflammation. The present study aims to investigate the underlying mechanism of miR-382-5p in the pathogenesis of RA. In present study, the decreased expression of miR-382-5p was observed in RA-FLSs. Furthermore, miR-382-5p overexpression inhibited the proliferation and invasion of RA-FLS cells. In addition, miR-382-5p overexpression inhibited the release of inflammatory cytokines and promoted apoptosis of RA-FLS cells. Finally, miR-382-5p overexpression induced inactivation of TLR4/NF-κB/Cox2 signaling pathway. Our findings implied that miR-382-5p exerts regulative effect on pathogenesis of RA and indicated that miR-382-5p may represent as an effective therapeutic target in the clinical treatment of RA.

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

Journal of Immunology Research ◽

10.1155/2016/6290682 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 22

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.

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Role of Fibroblast Activation Protein Alpha in Fibroblast-like Synoviocytes of Rheumatoid Arthritis

Iranian Journal of Allergy Asthma and Immunology ◽

10.18502/ijaai.v20i3.6335 ◽

2021 ◽

Author(s):

Mohammad Javad Mousavi ◽

Elham Farhadi ◽

Mohammad Vodjgani ◽

Jafar Karami ◽

Mohammad Naghi Tahmasebi ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Fibroblast Activation Protein ◽

Mrna Levels ◽

Pathogenic Role ◽

Fibroblast Activation ◽

Protein Levels ◽

Fibroblast Activation Protein Alpha ◽

Tgf Β1 ◽

Fibroblast Like Synoviocytes

Fibroblast-like synoviocytes (FLSs) have been introduced in recent years as a key player in the pathogenesis of rheumatoid arthritis (RA), but the exact mechanisms of their transformation and intracellular pathways have not yet been determined. This study aimed to investigate the role of fibroblast activation protein-alpha (FAP-α) in the regulation of genes involved in the transformation and pathogenic activity of RA FLSs. Synovial FLSs were isolated from RA patients and non-arthritic individuals (n=10 in both groups) and characterized; using immunocytochemistry and flow cytometry analysis. FLSs were divided into un-treated and Talabostat-treated groups to evaluate the FAP-α effect on the selected genes involved in cell cycle regulation (p21, p53, CCND1), apoptosis (Bcl-2, PUMA), and inflammatory and destructive behavior of FLSs (IL-6, TGF-β1, MMP-2, MMP-9, P2RX7). Gene expression analysis was performed by quantitative real-time polymerase chain reaction (qRTPCR), and immunoblotting was carried out to evaluate FAP-α protein levels. The basal level of FAP-α protein in RA patients was significantly higher than non-arthritic control individuals. However, no differences were observed between RA and non-arthritic FLSs, at the baseline mRNA levels of all the genes. Talabostat treatment significantly reduced FAPα protein levels in both RA and non-arthritic FLSs, however, had no effect on mRNA expressions except an upregulated TGF-β1 expression in non-arthritic FLSs. A significantly higher protein level of FAP-α in FLSs of RA patients compared with that of healthy individuals may point to the pathogenic role of this protein in RA FLSs. However, more investigations are necessary to address the mechanisms mediating the FAP-α pathogenic role in RA FLSs.

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