Citrullination enhances the pro-inflammatory response to fibrin in rheumatoid arthritis synovial fibroblasts

Sánchez‐Pernaute, Olga; Filková, Mária; Gabucio, Antonio; Klein, Martin; Maciejewska-Rodrigues, Hanna; Ospelt, Caroline; Brentano, Fabia; Michel, Beat A.; Gay, Renate E.; Herrero‐Beaumont, Gabriel; Gay, Steffen; Neidhart, Michel; Juengel, Astrid

doi:10.1136/annrheumdis-2012-201906

Cited by 56 publications

(45 citation statements)

References 49 publications

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“…Macromolecule synthesis is the main housekeeping function of immune cells (52). Macromolecule molecules participate in inducing expression of the proinflammatory cytokines (53). These cytokines, such as TNF-α, IL-1β, IL-6, IL-17 etc, have been demonstrated to promote osteoclast differentiation and function either directly or indirectly, by acting on cells of the osteoclastlineage or by acting on other cell types to regulate expression of the key osteoclastogenic factor receptor activator of nuclear factor kappaB ligand (RANKL) and/or its inhibitor osteoprotegerin (OPG) (54)(55).…”

Section: Discussionmentioning

confidence: 99%

microRNA Expression in Rat Apical Periodontitis Bone Lesion

Gao

2013

Bone Res.

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Apical periodontitis, dominated by dense inflammatory infiltrates and increased osteoclast activities, can lead to alveolar bone destruction and tooth loss. It is believed that miRNA participates in regulating various biological processes, osteoclastogenesis included. This study aims to investigate the differential expression of miRNAs in rat apical periodontitis and explore their functional target genes. Microarray analysis was used to identify differentially expressed miRNAs in apical periodontitis. Bioinformatics technique was applied for predicting the target genes of differentially expressed miRNAs and their biological functions. The result provided us with an insight into the potential biological effects of the differentially expressed miRNAs and showed particular enrichment of target genes involved in the MAPK signaling pathways. These findings may highlight the intricate and specific roles of miRNA in inflammation and osteoclastogenesis, both of which are key aspects of apical periodontitis, thus contributing to the future investigation into the etiology, underlying mechanism and treatment of apical periodontitis.

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Section: Discussionmentioning

confidence: 99%

microRNA Expression in Rat Apical Periodontitis Bone Lesion

Gao

2013

Bone Res.

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“…Interestingly, fibrin and other components of the extracellular matrix undergo citrullination in rheumatoid joints, and this posttranslational modification can further enhance mechanisms of cell activation, as has been demonstrated ( Figure 3) [22,[29][30][31]. In spite of not being specifically associated to the disease, this post-translational in rheumatoid synovial fibroblasts in the absence of collaboration of immune cells [22]. The fibrin transcriptome in these cells included some of the major pathogenic mediators of rheumatoid arthritis, such as interleukin 6, a variety of chemokines, vascular cell adhesion protein 1, intracellular adhesion molecule 1, tumor necrosis factor-related peptides, cyclooxygenase 2, and histone deacetylases.…”

Section: Fibrin Operates Ahead Of the Cytokine Networkmentioning

confidence: 72%

“…The number of potential targets within this route is therefore high, and probably differing between subgroups of patients. Interestingly, fibrin and other components of the extracellular matrix undergo citrullination in rheumatoid joints, and this posttranslational modification can further enhance mechanisms of cell activation, as has been demonstrated ( Figure 3) [22,[29][30][31]. In spite of not being specifically associated to the disease, this post-translational in rheumatoid synovial fibroblasts in the absence of collaboration of immune cells [22].…”

Section: Fibrin Operates Ahead Of the Cytokine Networkmentioning

confidence: 85%

“…The fibrin transcriptome in these cells included some of the major pathogenic mediators of rheumatoid arthritis, such as interleukin 6, a variety of chemokines, vascular cell adhesion protein 1, intracellular adhesion molecule 1, tumor necrosis factor-related peptides, cyclooxygenase 2, and histone deacetylases. As represented in Figure 3 (left panel) the toll-like receptor (TLR) 4 -nuclear factor kappa B axis was found to mediate fibrin-dependent gene induction in synovial fibroblasts, while a similar pathway had been drawn in macrophages [22][23][24]. Globally, these findings support that synovial cells might, through their interaction with fibrin, fuel the principal pathogenic processes of rheumatoid arthritis, acting upstream cytokine networks and lymphocyte activation (illustrated in Figure 3, main panel).…”

Section: Fibrin Operates Ahead Of the Cytokine Networkmentioning

confidence: 89%

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Targets Hidden by Fibrin Networks Still Need to Find Their Place in the Armamentarium for Rheumatoid Arthritis

Gabucio¹,

Sánchez‐Pernaute²

2016

HealthCare Current Reviews

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HCCR, an open access journal Page 3 of 4 modification of peptides facilitates their recognition as auto antigens [32]. Moreover, the development of antibodies to citrullinated peptides is relatively restricted to the disease. Citrullination is carried out by the family of peptidyl deiminases (PAD), out of which PAD2 emerges as an attractive therapeutic target. Of all isoforms, PAD2 shows the higher affinity for fibrin domains in vitro, and it has been found to be enriched in the synovial fluid of patients with rheumatoid arthritis and spondyloarthritis, as compared to osteoarthritis [33,34]. An increase in PAD has been put in relationship with erosive disease, and the presence of anti citrullinated antibodies is currently considered a marker of severe disease [35]. Altogether, this suggests that particular subgroups of patients would benefit from the inhibition of PAD2 activity. Limitations to the Development of Fibrin-Based TherapiesTwo major criticisms have hindered the progression of fibrin research in rheumatoid arthritis. The first one derived from the extrapolation of histopathological findings in synovial tissues from end-stage disease. Fibrin was for a long time considered a bystander product of inflammation. This hurdle was overcome with the studies performed in experimental models, and more recently, when fibrin was shown to be a major auto antigen of the disease. The second point raised was the lack of specificity of intra-articular fibrin deposition. This drawback is shared by most studies approaching the invasive phenotype of rheumatoid synovial fibroblasts, which have failed to show intrinsic alterations. In concordance, our group has found a similar profile of gene induction in fibroblasts from osteoarthritic joints to the one depicted by rheumatoid fibroblasts upon exposure to fibrin (unpublished data). This rather supports that fibrin networks provide a micro environmental imprinting, as responsible for the aggressive features of these cells. Besides, we did observe differences in the magnitude of the cell response between both conditions, probably due to the higher expression level of TLR4 in rheumatoid as compared to osteoarthritic synovial fibroblasts, as has been observed [25,26].In conclusion, complexity of rheumatoid arthritis warrants a multi-target approach in order to shut down mechanisms involved in disease progression. In the next future, a better characterization of each phenotype will facilitate the use of tailored strategies, in which a place for fibrin-based therapies can be forecasted. AcknowledgementThe authors' work was supported by the Conchita Rabago Foundation.

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“…It is an autoimmune disease in which immune system attacks joints result in inflammation. It occurs in age 30 and 60 in women and in man it occurs later [21].…”

Section: Rheumatoid Arthritis (Ra)mentioning

confidence: 99%

Fibrinolytic Enzyme: Restoration Tool for Obliteration of Blood Clots

Ashraf¹,

Meer²,

Naz³

et al. 2017

J Mol Imaging Dynam

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Body interrelated complex system maintain body hemostasis but severe vascular injury reprehensible for thrombus formation. Fibrinogen is a prime protein in fibrinolysis. Complex cascade pathway involves in conversion of plasminogen to plasmin to perform fibrinolysis and plasminogen activating inhibitor (PAI) cease this pathway. The genetic and acquired factors influence clot formation while it curbs by factor VIII. This review aims to illustrate significance of fibrinolytic enzymes, Nattokinase, Urokinase, Staphylokinase and streptokinase as therapeutic agent to control myocardial infraction, venous stroke and pulmonary clotting.

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Citrullination enhances the pro-inflammatory response to fibrin in rheumatoid arthritis synovial fibroblasts

Abstract: Our results suggest that fibrin mediates inflammatory responses in RASF via a TLR4 pathway. In this way, fibrin and particularly its citrullinated form may contribute to sustain the cytokine burst in RA.

Cited by 56 publications

References 49 publications

microRNA Expression in Rat Apical Periodontitis Bone Lesion

microRNA Expression in Rat Apical Periodontitis Bone Lesion

Targets Hidden by Fibrin Networks Still Need to Find Their Place in the Armamentarium for Rheumatoid Arthritis

Fibrinolytic Enzyme: Restoration Tool for Obliteration of Blood Clots

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