Transcription Factor Snail Regulates Tumor Necrosis Factor α–Mediated Synovial Fibroblast Activation in the Rheumatoid Joint

Chen, Shih-Yao; Shiau, Ai‐Li; Li, Yuan-Tsung; Lin, Chi-Chen; Jou, I‐Ming; Liu, Ming-Fei; Wu, Chao‐Liang; Wang, Chrong‐Reen

doi:10.1002/art.38899

Cited by 27 publications

(52 citation statements)

References 46 publications

(60 reference statements)

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“…21,22,24,27 In a recent study, Snail overexpression was shown to increase cytokine expression and invasiveness of rat synovial cells, resulting in the exacerbation of CIA. 35 In this study, we highlight the direct implication of Snail1 that acts as a key effector of ECM degradation in arthritic FLS by promoting invadosome formation. Snail was specifically associated with the FLS subpopulation responsible for active matrix degradation and overexpressed in synovial membranes of CIA joints.…”

Section: Synoviocytes Reactivate Snail To Gain Their Invadosome-formimentioning

confidence: 83%

“…32e34 In addition, a recent study indicates that Snail is overexpressed in synovium and cell lines from RA patients. 35 In light of the above findings, we hypothesized that fibroblast-like synovial cells use components or pathways of the EMT program to promote invadosome formation, leading to arthritis progression toward a more destructive phenotype. Data shown herein provide evidence that the Snail transcriptional regulator is essential for ECM degradation by human and rat synovial cells and for cartilage degradation in a CIA model.…”

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confidence: 99%

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Snail Is a Critical Mediator of Invadosome Formation and Joint Degradation in Arthritis

Lauzier

Lavoie

Charbonneau

et al. 2016

The American Journal of Pathology

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Progressive cartilage destruction, mediated by invasive fibroblast-like synoviocytes, is a central feature in the pathogenesis of rheumatoid arthritis (RA). Members of the Snail family of transcription factors are required for cell migration and invasion, but their role in joint destruction remains unknown. Herein, we demonstrate that Snail is essential for the formation of extracellular matrix-degrading invadosomal structures by synovial cells from collagen-induced arthritis (CIA) rats and RA patients. Mechanistically, Snail induces extracellular matrix degradation in synovial cells by repressing PTEN, resulting in increased phosphorylation of platelet-derived growth factor receptor and activation of the phosphatidylinositol 3-kinase/AKT pathway. Of significance, Snail is overexpressed in synovial cells and tissues of CIA rats and RA patients, whereas knockdown of Snail in CIA joints prevents cartilage invasion and joint damage. Furthermore, Snail expression is associated with an epithelial-mesenchymal transition gene signature characteristic of transglutaminase 2/transforming growth factor-β activation. Transforming growth factor-β and transglutaminase 2 stimulate Snail-dependent invadosome formation in rat and human synoviocytes. Our results identify the Snail-PTEN platelet-derived growth factor receptor/phosphatidylinositol 3-kinase axis as a novel regulator of the prodestructive invadosome-forming phenotype of synovial cells. New therapies for RA target inflammation, and are only partly effective in preventing joint damage. Blocking Snail and/or its associated gene expression program may provide an additional tool to improve the efficacy of treatments to prevent joint destruction.

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Section: Synoviocytes Reactivate Snail To Gain Their Invadosome-formimentioning

confidence: 83%

mentioning

confidence: 99%

Snail Is a Critical Mediator of Invadosome Formation and Joint Degradation in Arthritis

Lauzier

Lavoie

Charbonneau

et al. 2016

The American Journal of Pathology

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“…To induce CAIA, male 8‐week‐old DBA/1J mice received IP injections of a 5‐clone monoclonal antibody cocktail (Chondrex) on day 0, followed by IP injections of lipopolysaccharide on day 3. Synovial tissue from mice with CIA was treated with collagenase, and isolated SFs were cultured continuously until confluence was reached, with cells from passages 4–7 being used in further experiments .…”

Section: Methodsmentioning

confidence: 99%

Amelioration of Experimental Autoimmune Arthritis Through Targeting of Synovial Fibroblasts by Intraarticular Delivery of MicroRNAs 140‐3p and 140‐5p

Peng

Chen

et al. 2016

Arthritis & Rheumatology

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Objective Synovial fibroblasts (SFs) with aberrant expression of microRNAs (miRNAs) are critical pathogenic regulators in rheumatoid arthritis (RA), and studies analyzing the effect of overexpressing or silencing miRNA expression in arthritis models can contribute to the development of miRNA‐based therapeutic strategies. This study was undertaken to examine the hypothesis that miRNAs 140‐3p and 140‐5p are involved in the pathogenesis of RA, and to determine whether targeting SFs through the intraarticular (IA) delivery of these molecules could ameliorate autoimmune arthritis in mice. Methods Synovial tissue samples were obtained from patients with RA. In addition, 2 experimental models in mice were used, collagen‐induced arthritis (CIA) and collagen antibody–induced arthritis (CAIA). Overexpression of miRNAs 140‐3p and 140‐5p in SFs and synovial tissue was induced using lentivirus (LV)–mediated transfer of pre‐miR‐140 precursor molecules. Results Lower expression levels of miR‐140‐3p and miR‐140‐5p were detected in synovial tissue and SFs from patients with RA and from mice in both arthritis models. In mice with CIA and mice with CAIA, the LV‐mediated IA transfer of miR‐140‐3p and miR‐140‐5p ameliorated arthritis, as determined by clinical examination and histopathologic evaluations showing a decrease in SF densities. Overexpression of miRNAs 140‐3p and 140‐5p caused a reduction in expression, with correlated kinetic patterns, of their corresponding target molecules sirtuin 1 and stromal cell–derived factor 1 in the SFs and joints of mice. Transfection of miR‐140‐3p and miR‐140‐5p into SFs increased cell apoptosis, reduced proliferation responses and migration abilities, and verified the concept that miR‐140 expression is regulated by proinflammatory cytokines. Conclusion These results demonstrate that targeting SFs by IA delivery of miRNAs 140‐3p and 140‐5p can ameliorate autoimmune arthritis. These findings might facilitate the pharmacologic development of molecular‐based therapies in RA.

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“…Recombinant lentiviral vectors, LVshTLR4, LVMyD88, LVshLuc, and LVGFP were produced by transient transfection of 293T cells with pLKO.1-shTLR4, pLKO.1-shMyD88, pLKO.1-shLuc, and pWPT respectively, along with the packaging plasmid psPAX2 and the envelope plasmid pMD2G, as previously described29. The viral titers were determined by using cell viability assay with A549 cells to calculate relative infection unit (RIU) based on the protocol of the National RNAi Core Facility29. On the basis of qRT-PCR analysis, we chose pLKO.1-shTLR4#2 and pLKO.1-shMyD88#2 plasmids (TRCN0000065786 and TRCN0000077234) to generate lentiviral vectors that encoded TLR4 and MyD88 shRNA.…”

Section: Methodsmentioning

confidence: 99%

“…To produce TLR4- or MyD88- knocked down stable transfectants, mouse bladder carcinoma MBT2 cells were transduced with LVshTLR4 or LVshMyD88 for 48 h, respectively, in the presence of 8 μg/ml polybrene (Sigma-Aldrich, St. Louis, MO), and the cells were then incubated with puromycin (2 μg/ml) for 2 weeks. Control transfectants were obtained by transduction with LVshLuc, followed by puromycin selection29.…”

Section: Methodsmentioning

confidence: 99%

Knockdown of toll-like receptor 4 signaling pathways ameliorate bone graft rejection in a mouse model of allograft transplantation

Hsieh

Shen

et al. 2017

Sci Rep

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Non-union occurring in structural bone grafting is a major problem in allograft transplantation because of impaired interaction between the host and graft tissue. Activated toll-like receptor (TLR) induces inflammatory cytokines and chemokines and triggers cell-mediated immune responses. The TLR-mediated signal pathway is important for mediating allograft rejection. We evaluated the effects of local knockdown of the TLR4 signaling pathway in a mouse segmental femoral graft model. Allografts were coated with freeze-dried lentiviral vectors that encoded TLR4 and myeloid differentiation primary response gene 88 (MyD88) short-hairpin RNA (shRNA), which were individually transplanted into the mice. They were assessed morphologically, radiographically, and histologically for tissue remodeling. Union occurred in autografted but not in allografted mice at the graft and host junctions after 4 weeks. TLR4 and MyD88 expression was up-regulated in allografted mice. TLR4 and MyD88 shRNAs inhibited TLR4 and MyD88 expression, which led to better union in the grafted sites. More regulatory T-cells in the draining lymph nodes suggested inflammation suppression. Local inhibition of TLR4 and MyD88 might reduce immune responses and ameliorate allograft rejection.

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Transcription Factor Snail Regulates Tumor Necrosis Factor α–Mediated Synovial Fibroblast Activation in the Rheumatoid Joint

Cited by 27 publications

References 46 publications

Snail Is a Critical Mediator of Invadosome Formation and Joint Degradation in Arthritis

Snail Is a Critical Mediator of Invadosome Formation and Joint Degradation in Arthritis

Amelioration of Experimental Autoimmune Arthritis Through Targeting of Synovial Fibroblasts by Intraarticular Delivery of MicroRNAs 140‐3p and 140‐5p

Knockdown of toll-like receptor 4 signaling pathways ameliorate bone graft rejection in a mouse model of allograft transplantation

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