Role of the Netrin System of Repellent Factors on Synovial Fibroblasts in Rheumatoid Arthritis and Osteoarthritis

Prostaglandin (PG)I2 (prostacyclin [PGI]) and PGE2 are abundantly present in the synovial fluid of rheumatoid arthritis (RA) patients. Although the role of PGE2 in RA has been well studied, how much PGI2 contributes to RA is little known. To examine this issue, we backcrossed mice lacking the PGI receptor (IP) to the DBA/1J strain and subjected them to collagen-induced arthritis (CIA). IP-deficient (IP−/−) mice exhibited significant reduction in arthritic scores compared with wild-type (WT) mice, despite anti-collagen antibody production and complement activation similar to WT mice. IP−/− mice also showed significant reduction in contents of proinflammatory cytokines, such as interleukin (IL)-6 in arthritic paws. Consistently, the addition of an IP agonist to cultured synovial fibroblasts significantly enhanced IL-6 production and induced expression of other arthritis-related genes. On the other hand, loss or inhibition of each PGE receptor subtype alone did not affect elicitation of inflammation in CIA. However, a partial but significant suppression of CIA was achieved by the combined inhibition of EP2 and EP4. Our results show significant roles of both PGI2-IP and PGE2-EP2/EP4 signaling in the development of CIA, and suggest that inhibition of PGE2 synthesis alone may not be sufficient for suppression of RA symptoms.

Download Full-text

Dual Role of Autophagy in Stress-Induced Cell Death in Rheumatoid Arthritis Synovial Fibroblasts

Arthritis & Rheumatology ◽

10.1002/art.38190 ◽

2013 ◽

Vol 66 (1) ◽

pp. 40-48 ◽

Cited By ~ 69

Author(s):

Masaru Kato ◽

Caroline Ospelt ◽

Renate E. Gay ◽

Steffen Gay ◽

Kerstin Klein

Keyword(s):

Rheumatoid Arthritis ◽

Cell Death ◽

Synovial Fibroblasts ◽

Dual Role

Download Full-text

Lipid Peroxidation-Mediated Inflammation Promotes Cell Apoptosis through Activation of NF-κB Pathway in Rheumatoid Arthritis Synovial Cells

Mediators of Inflammation ◽

10.1155/2015/460310 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 27

Author(s):

Geng Yin ◽

Ying Wang ◽

Xiao-min Cen ◽

Min Yang ◽

Yan Liang ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Cell Apoptosis ◽

Inflammatory Responses ◽

Synovial Fibroblasts ◽

Systemic Autoimmune Disease ◽

New Strategy ◽

Significant Clinical Improvement ◽

Rheumatoid Arthritis Synoviocytes ◽

Initiation Of Therapy

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of multiple joints. The central pathogenesis of RA is the proliferation of synovial fibroblasts in response to inflammatory cytokines. However, some of the targeted therapies for inflammation reactions do not display significant clinical improvement after initiation of therapy. Thus, the relationship between inflammatory responses and RA therapy is still incompletely understood. In the present study, we proposed to determine whether enhanced inflammations may lead to cell apoptosis in rheumatoid arthritis synoviocytes. Our results indicated that products of lipid peroxidations, 4-HNE, may induce synovial intrinsic inflammations by activating NF-κB pathways and it may lead to cell apoptosis. Pharmacological inhibition of NF-κB activation may reduce the 4-HNE mediated inflammation responses and subsequent cell apoptosis. Our results may help to clarify the role of inflammations on RA development and imply that blocking NF-κB activation may be partly beneficial for human RA therapy. These findings might provide a mechanism-based rationale for developing new strategy to RA clinical therapy.

Download Full-text

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

The Journal of Rheumatology ◽

10.3899/jrheum.170170 ◽

2017 ◽

Vol 45 (3) ◽

pp. 335-340 ◽

Cited By ~ 1

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).

Download Full-text

AB0071 Dual role of autophagy in stress-induced cell death in rheumatoid arthritis synovial fibroblasts

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2013-eular.2394 ◽

2013 ◽

Vol 72 (Suppl 3) ◽

pp. A807.2-A807

Author(s):

M. Kato ◽

C. Ospelt ◽

B. A. Michel ◽

R. E. Gay ◽

S. Gay ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Cell Death ◽

Synovial Fibroblasts ◽

Dual Role

Download Full-text

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.

Download Full-text

CUX1 and IκBζ (NFKBIZ) mediate the synergistic inflammatory response to TNF and IL-17A in stromal fibroblasts

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1912702117 ◽

2020 ◽

Vol 117 (10) ◽

pp. 5532-5541 ◽

Cited By ~ 1

Author(s):

Kamil Slowikowski ◽

Hung N. Nguyen ◽

Erika H. Noss ◽

Daimon P. Simmons ◽

Fumitaka Mizoguchi ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Transcriptional Response ◽

Synovial Fibroblasts ◽

Binding Motif ◽

Minimal Effect ◽

Stromal Fibroblasts ◽

Monocyte Recruitment ◽

Synergistic Response ◽

Dose Dependent

The role of stromal fibroblasts in chronic inflammation is unfolding. In rheumatoid arthritis, leukocyte-derived cytokines TNF and IL-17A work together, activating fibroblasts to become a dominant source of the hallmark cytokine IL-6. However, IL-17A alone has minimal effect on fibroblasts. To identify key mediators of the synergistic response to TNF and IL-17A in human synovial fibroblasts, we performed time series, dose–response, and gene-silencing transcriptomics experiments. Here we show that in combination with TNF, IL-17A selectively induces a specific set of genes mediated by factors including cut-like homeobox 1 (CUX1) and IκBζ (NFKBIZ). In the promoters of CXCL1, CXCL2, and CXCL3, we found a putative CUX1–NF-κB binding motif not found elsewhere in the genome. CUX1 and NF-κB p65 mediate transcription of these genes independent of LIFR, STAT3, STAT4, and ELF3. Transcription of NFKBIZ, encoding the atypical IκB factor IκBζ, is IL-17A dose-dependent, and IκBζ only mediates the transcriptional response to TNF and IL-17A, but not to TNF alone. In fibroblasts, IL-17A response depends on CUX1 and IκBζ to engage the NF-κB complex to produce chemoattractants for neutrophil and monocyte recruitment.

Download Full-text

SAT0024 JAK-INHIBITION WITH BARICTINIB INHIBITS ACTIVATION OF NLRP1/CASPASE1/GDMSD PYROPTOSIS PATHWAY IN RHEUMATOID ARTHRITIS SYNOVIAL FIBROBLASTS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.5062 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 942.1-942

Author(s):

W. Xie ◽

Z. Zhang

Keyword(s):

Rheumatoid Arthritis ◽

Small Interfering Rna ◽

Synovial Fibroblasts ◽

Inflammasome Activation ◽

Activity Levels ◽

Dependent Manner ◽

Hematopoietic Progenitor ◽

Caspase 1 ◽

Interfering Rna

Background:Synovial fibroblasts (SFs) play a major role in the pathogenesis of rheumatoid arthritis (RA) and develop an aggressive phenotype destroying cartilage and bone, thus termed RASFs.Objectives:We aim to examine the presence of GSDMD-mediated pyroptosis and its role in activated RASFs.Methods:Fibroblasts were isolated from RA synovium obtained from knee replacement surgeries. NLRP1, Caspase-1, GSDMD expression in synovial tissue and TNF-treated RASFs were assessed by qPCR and Western blot. Interleukin (IL)-1 was measured by ELISA in supernatant after pretreated with TNF and barictinib. LDH release was measured using the CytoTox 96 Non-Radioactive Cytotoxicity Assay Kit. Endogenous NLRP1, Caspase-1, and GSDMD was knocked down using small interfering RNA.Results:The expressions of NLRP1, pro-Caspase-1, Caspase-1 p10, GSDMD and its pyroptosis-inducing fragment GSDMD-N were greater in RA synovium than OA synovium. TNF-induced NLRP1, pro-Caspase-1, Caspase-1 p10, GSDMD, and GSDMD-N expression at the transcript and protein level in a time-dependent manner (P < 0.05). Meanwhile, the release of LDH and IL-1 were significantly increased in RASFs after treated with TNF. We also confirmed the presence of pyroptosis in electron microscopy. Furthermore, blocking the JAK pathway with barictinib significantly reduced TNF-induced pyroptosis at the transcriptional, protein and activity levels (P < 0.05). Finally, blocking the JAK pathway, we observed a reduction of IL-1 bioactivity in RASFs (P < 0.05).Conclusion:Our results demonstrate an important role of GSDMD-mediated pyroptosis and shed lights on a potential pyroptosis-targeted treatment. Meanwhile, JAK inhibition alleviates inflammasome-induced pyroptosis by blocking pyroptosis pathway in RASFs.References:[1] Masters, S. L. et al. NLRP1 inflammasome activation induces pyroptosis of hematopoietic progenitor cells. Immunity,2012,37:1009–1023.Disclosure of Interests:None declared

Download Full-text