scholarly journals The activation fragment of PAR2 is elevated in serum from patients with rheumatoid arthritis and reduced in response to anti-IL6R treatment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Stefania Kalogera ◽  
Yi He ◽  
Anne-Christine Bay-Jensen ◽  
Thorbjørn Gantzel ◽  
Shu Sun ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Serine Proteases ◽  
Serum Levels ◽  
Cartilage Destruction ◽  
Synovial Hyperplasia ◽  
Amino Acid Peptide ◽  
Potential Biomarker ◽  
Protease Activated Receptor 2 ◽  
Inter Assay Variation

AbstractOsteoarthritis (OA) and rheumatoid arthritis (RA) are serious and painful diseases. Protease-activated receptor 2 (PAR2) is involved in the pathology of both OA and RA including roles in synovial hyperplasia, cartilage destruction, osteophyogenesis and pain. PAR2 is activated via cleavage of its N-terminus by serine proteases. In this study a competitive ELISA assay was developed targeting the 36-amino acid peptide that is cleaved and released after PAR2 activation (PRO-PAR2). Technical assay parameters including antibody specificity, intra- and inter-assay variation (CV%), linearity, accuracy, analyte stability and interference were evaluated. PRO-PAR2 release was confirmed after in vitro cleavage of PAR2 recombinant protein and treatment of human synovial explants with matriptase. Serum levels of 22 healthy individuals, 23 OA patients and 15 RA patients as well as a subset of RA patients treated with tocilizumab were evaluated. The PRO-PAR2 antibody was specific for the neo-epitope and intra-inter assay CV% were 6.4% and 5.8% respectively. In vitro cleavage and matriptase treated explants showed increased PRO-PAR2 levels compared to controls. In serum, PRO-PAR2 levels were increased in RA patients and decreased in RA patients treated with tocilizumab. In conclusion, PRO-PAR2 may be a potential biomarker for monitoring RA disease and pharmacodynamics of treatment.

scholarly journals The Activation Fragment of PAR2 Is Increased in RA and Modulated in Response To Anti-IL-6R Treatment

2021 ◽  
Author(s):  
Stefania Kalogera ◽  
Yi He ◽  
Anne-Christine Bay-Jensen ◽  
Thorbjørn Gantzel ◽  
Shu Sun ◽  
...  
Keyword(s):  
Serine Proteases ◽  
Serum Levels ◽  
Cartilage Destruction ◽  
Synovial Hyperplasia ◽  
Amino Acid Peptide ◽  
Potential Biomarker ◽  
Protease Activated Receptor 2 ◽  
Inter Assay Variation ◽  
Synovial Explants

Abstract Osteoarthritis (OA) and rheumatoid arthritis (RA) are serious and painful diseases. Protease-activated receptor 2 (PAR2) is involved in the pathology of both OA and RA including roles in synovial hyperplasia, cartilage destruction, osteophyogenesis and pain. PAR2 is activated via cleavage of its N-terminus by serine proteases. In this study a competitive ELISA assay was developed targeting the 36-amino acid peptide that is cleaved and released after PAR2 activation. Technical assay parameters including antibody specificity, intra- and inter-assay variation (CV%), linearity, accuracy, analyte stability and interference were evaluated. PAR2 pro-fragment release was confirmed after in vitro cleavage of PAR2 recombinant protein and treatment of human synovial explants with matriptase. Serum levels of 22 healthy individuals, 23 OA patients and 15 RA patients as well as a subset of RA patients treated with tocilizumab were evaluated. The PAR2 antibody was specific for the neo-epitope and intra-inter assay CV% were 6.4% and 5.8% respectively. In vitro cleavage and matriptase treated explants showed increased PAR2 pro-fragment levels compared to controls. In serum, PAR2 pro-fragment levels were increased in RA patients and decreased in RA patients treated with tocilizumab. In conclusion, PAR2 may be a potential biomarker for monitoring RA disease and pharmacodynamics of treatment.

scholarly journals The Role of Collagen Triple Helix Repeat-Containing 1 Protein (CTHRC1) in Rheumatoid Arthritis

2021 ◽  
Vol 22 (5) ◽  
pp. 2426
Author(s):  
Askhat Myngbay ◽  
Limara Manarbek ◽  
Steve Ludbrook ◽  
Jeannette Kunz
Keyword(s):  
Rheumatoid Arthritis ◽  
Drug Targets ◽  
Triple Helix ◽  
Cancer Metastasis ◽  
Bone Erosion ◽  
Cartilage Destruction ◽  
Patient Treatment ◽  
Collagen Triple Helix ◽  
Potential Biomarker

Rheumatoid arthritis (RA) is a chronic autoimmune disease causing inflammation of joints, cartilage destruction and bone erosion. Biomarkers and new drug targets are actively sought and progressed to improve available options for patient treatment. The Collagen Triple Helix Repeat Containing 1 protein (CTHRC1) may have an important role as a biomarker for rheumatoid arthritis, as CTHRC1 protein concentration is significantly elevated in the peripheral blood of rheumatoid arthritis patients compared to osteoarthritis (OA) patients and healthy individuals. CTHRC1 is a secreted glycoprotein that promotes cell migration and has been implicated in arterial tissue-repair processes. Furthermore, high CTHRC1 expression is observed in many types of cancer and is associated with cancer metastasis to the bone and poor patient prognosis. However, the function of CTHRC1 in RA is still largely undefined. The aim of this review is to summarize recent findings on the role of CTHRC1 as a potential biomarker and pathogenic driver of RA progression. We will discuss emerging evidence linking CTHRC1 to the pathogenic behavior of fibroblast-like synoviocytes and to cartilage and bone erosion through modulation of the balance between bone resorption and repair.

scholarly journals PTEN Methylation Promotes Inflammation and Activation of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiao-Feng Li ◽  
Sha Wu ◽  
Qi Yan ◽  
Yuan-Yuan Wu ◽  
He Chen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Articular Cartilage ◽  
Dna Methyltransferase ◽  
Underlying Mechanism ◽  
Cartilage Destruction ◽  
Specific Pcr ◽  
Methylation Inhibitor ◽  
Fibroblast Like Synoviocytes

Rheumatoid arthritis (RA) is characterized by a tumor-like expansion of the synovium and subsequent destruction of adjacent articular cartilage and bone. In our previous work we showed that phosphatase and tension homolog deleted on chromosome 10 (PTEN) contributes to the activation of fibroblast-like synoviocytes (FLS) in adjuvant-induced arthritis (AIA), but the underlying mechanism is not unknown. In this study, we show that PTEN is downregulated while DNA methyltransferase (DNMT)1 is upregulated in FLS from RA patients and a rat model of AIA. DNA methylation of PTEN was increased by administration of tumor necrosis factor (TNF)-α in FLS of RA patients, as determined by chromatin immunoprecipitation and methylation-specific PCR. Treatment with the methylation inhibitor 5-azacytidine suppressed cytokine and chemokine release and FLS activation in vitro and alleviated paw swelling in vivo. PTEN overexpression reduced inflammation and activation of FLS via protein kinase B (AKT) signaling in RA, and intra-articular injection of PTEN-expressing adenovirus into the knee of AIA rats markedly reduced inflammation and paw swelling. Thus, PTEN methylation promotes the inflammation and activation of FLS in the pathogenesis of RA. These findings provide insight into the molecular basis of articular cartilage destruction in RA, and indicate that therapeutic strategies that prevent PTEN methylation may an effective treatment.

scholarly journals The macrophage reprogramming ability of antifolates reveals soluble CD14 as a potential biomarker for methotrexate response in rheumatoid arthritis

2021 ◽  
Author(s):  
Sara Fuentelsaz-Romero ◽  
Celia Barrio Alonso ◽  
Raquel Garcia Campos ◽  
Monica Torres Torresano ◽  
Ittai Muller ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Human Monocyte ◽  
Serum Levels ◽  
Gene Signature ◽  
Soluble Cd14 ◽  
Potential Biomarker ◽  
Exogenous Addition ◽  
Proinflammatory Gene ◽  
One Carbon Metabolism ◽  
The One

The physio-pathological relevance of the one-carbon metabolism (OCM) is illustrated by the chemotherapeutic and anti-inflammatory effects of the antifolates Pemetrexed (PMX) and Methotrexate (MTX) in cancer and rheumatoid arthritis (RA). We report that OCM determines the functional and gene expression profile of human macrophages. PMX induces the acquisition of a p53-dependent proinflammatory gene signature in human monocyte-derived macrophages (GM-Mθ). Indeed, OCM blockade reprograms GM-Mθ towards a state of LPS-tolerance at the signaling and functional levels, an effect abolished by folinic acid. Importantly, OCM blockade led to reduced expression of membrane-bound and soluble CD14 (sCD14), whose exogenous addition restores LPS sensitivity. The therapeutic relevance of these results was confirmed in early RA patients, as MTX-responder RA patients exhibit lower sCD14 serum levels, with baseline sCD14 levels predicting MTX response. Our results indicate that OCM is a metabolic circuit that critically mediates the acquisition of innate immune tolerance, and positions sCD14 as a valuable tool to predict MTX-response in RA patients.

scholarly journals Circulating miRNA-125b Is a Potential Biomarker Predicting Response to Rituximab in Rheumatoid Arthritis

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Isabelle Duroux-Richard ◽  
Yves-Marie Pers ◽  
Sylvie Fabre ◽  
Meryem Ammari ◽  
Dominique Baeten ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Predictive Value ◽  
Predictive Biomarker ◽  
Serum Levels ◽  
High Serum ◽  
Response To Treatment ◽  
Serum Samples ◽  
Total Blood ◽  
Novel Mirna ◽  
Potential Biomarker

Although biologic therapies have changed the course of rheumatoid arthritis (RA), today’s major challenge remains to identify biomarkers to target treatments to selected patient groups. Circulating micro(mi)RNAs represent a novel class of molecular biomarkers whose expression is altered in RA. Our study aimed at quantifying miR-125b in blood and serum samples from RA patients, comparing healthy controls and patients with other forms of rheumatic diseases and arthritis, and evaluating its predictive value as biomarker for response to rituximab. Detectable levels of miR-125b were measured in total blood and serum samples and were significantly elevated in RA patients compared to osteoarthritic and healthy donors. The increase was however also found in patients with other forms of chronic inflammatory arthritis. Importantly, high serum levels of miR-125b at disease flare were associated with good clinical response to treatment with rituximab three months later (P=0.002). This predictive value was not limited to RA as it was also found in patients with B lymphomas. Our results identify circulating miR-125b as a novel miRNA over expressed in RA and suggest that serum level of miR-125b is potential predictive biomarker of response to rituximab treatment.

scholarly journals Galectin-9 Is a Possible Promoter of Immunopathology in Rheumatoid Arthritis by Activation of Peptidyl Arginine Deiminase 4 (PAD-4) in Granulocytes

2019 ◽  
Vol 20 (16) ◽  
pp. 4046 ◽  
Author(s):  
Valerie R. Wiersma ◽  
Alex Clarke ◽  
Simon D. Pouwels ◽  
Elizabeth Perry ◽  
Trefa M. Abdullah ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Serum Levels ◽  
Arginine Deiminase ◽  
Joint Disease ◽  
Protein Levels ◽  
Reactive Protein ◽  
Peptidyl Arginine Deiminase ◽  
Key Enzyme ◽  
Immunomodulatory Protein

The aetiology of rheumatoid arthritis (RA) is unknown, but citrullination of proteins is thought to be an initiating event. In addition, it is increasingly evident that the lung can be a potential site for the generation of autoimmune triggers before the development of joint disease. Here, we identified that serum levels of galectin-9 (Gal-9), a pleiotropic immunomodulatory protein, are elevated in RA patients, and are even further increased in patients with comorbid bronchiectasis, a lung disease caused by chronic inflammation. The serum concentrations of Gal-9 correlate with C-reactive protein levels and DAS-28 score. Gal-9 activated polymorphonuclear leukocytes (granulocytes) in vitro, which was characterized by increased cytokine secretion, migration, and survival. Further, granulocytes treated with Gal-9 upregulated expression of peptidyl arginine deiminase 4 (PAD-4), a key enzyme required for RA-associated citrullination of proteins. Correspondingly, treatment with Gal-9 triggered citrullination of intracellular granulocyte proteins that are known contributors to RA pathogenesis (i.e., myeloperoxidase, alpha-enolase, MMP-9, lactoferrin). In conclusion, this study identifies for the first time an immunomodulatory protein, Gal-9, that triggers activation of granulocytes leading to increased PAD-4 expression and generation of citrullinated autoantigens. This pathway may represent a potentially important mechanism for development of RA.

scholarly journals Repurposing of Pirfenidone (Anti-Pulmonary Fibrosis Drug) for Treatment of Rheumatoid Arthritis

2021 ◽  
Vol 12 ◽  
Author(s):  
Donghao Gan ◽  
Wenxiang Cheng ◽  
Liqing Ke ◽  
Antonia RuJia Sun ◽  
Qingyun Jia ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Articular Chondrocytes ◽  
Joint Destruction ◽  
Pathological Process ◽  
Therapeutic Drug ◽  
Pathological Changes ◽  
Synovial Hyperplasia ◽  
Tnf Α ◽  
And Migration

Clinical studies have shown that pirfenidone (PFD) effectively relieves joint pain in rheumatoid arthritis (RA) patients. However, the detailed mechanisms underlying the anti-RA effects of PFD have not been investigated. This study was undertaken to investigate the repurposing of PFD for the treatment of RA, and explore its anti-rheumatic mechanisms. A collagen-induced arthritis (CIA) rat model was used to observe joint pathological changes following PFD treatment. Based on bioinformatics to predict the mechanism of PFD anti-RA, using EA. hy926 and TNF-α-induced MH7A cells to establish in vitro model to explore its biological mechanism from the perspectives of synovial inflammation and angiogenesis. PFD significantly relieved pathological changes, including joint swelling, synovial hyperplasia, inflammatory cell infiltration and joint destruction. PFD was also associated with reduced expression of MMP-3 and VEGF in articular chondrocytes and synovial cells of CIA rats (p < 0.05). Using bioinformatic methods, we predicted that PFD inhibits cell inflammation and migration by interfering with the JAK2/STAT3 and Akt pathways. These results were verified using in vitro models. In particular, PFD effectively reduced the expression of pro-inflammatory, chondrogenic, and angiogenic cytokines, such as IL-1β, IL-6, IL-8, MMP-1/3/2/9 and VEGF (p < 0.05), in TNF-α-induced MH7A cells. In addition, PFD significantly reduced the production of MMP-2/9 and VEGF in EA. hy926 cells, thereby weakening migration and inhibiting angiogenesis (p < 0.05). These findings suggest that PFD may alleviate the pathological process in CIA rats, by inhibiting inflammation and angiogenesis through multiple pathways, and serve as a potential therapeutic drug for RA.

scholarly journals Dual Role of Chondrocytes in Rheumatoid Arthritis: The Chicken and the Egg

2020 ◽  
Vol 21 (3) ◽  
pp. 1071 ◽  
Author(s):  
Chia-Chun Tseng ◽  
Yi-Jen Chen ◽  
Wei-An Chang ◽  
Wen-Chan Tsai ◽  
Tsan-Teng Ou ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Current Knowledge ◽  
Cartilage Destruction ◽  
Molecular Alterations ◽  
Diagnosis And Prognosis ◽  
Potential Applications ◽  
Biochemical Mechanisms ◽  
Holistic Vision

Rheumatoid arthritis (RA) is one of the inflammatory joint diseases that display features of articular cartilage destruction. The underlying disturbance results from immune dysregulation that directly and indirectly influence chondrocyte physiology. In the last years, significant evidence inferred from studies in vitro and in the animal model offered a more holistic vision of chondrocytes in RA. Chondrocytes, despite being one of injured cells in RA, also undergo molecular alterations to actively participate in inflammation and matrix destruction in the human rheumatoid joint. This review covers current knowledge about the specific cellular and biochemical mechanisms that account for the chondrocyte signatures of RA and its potential applications for diagnosis and prognosis in RA.

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