Association of ITGAV supports a role of angiogenesis in rheumatoid arthritis.
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ABSTRACT:
SUBMITTER: Ahnert P
PROVIDER: S-EPMC2212585 | biostudies-literature | 2007
REPOSITORIES: biostudies-literature
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Association of ITGAV supports a role of angiogenesis in rheumatoid arthritis.
Ahnert Peter P Kirsten Holger H
Arthritis research & therapy 20070101 5
Motivated by linkage data and the hypothesis that angiogenesis plays a functional role in rheumatoid arthritis (RA), Jacq and colleagues present a family-based, multi-stage, candidate gene association study in French and European Caucasians in a paper on the association of the ITGAV rs3738919-C variant allele with RA (C-containing genotypes: odds ratio 1.94, confidence interval 1.3 to 2.9, P = 0.002). Support comes from a recent genome-wide study, which on its own would have missed identifying t ...[more]
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Project description:To determine the role of CCL21 and its receptor CCR7 in the pathogenesis of rheumatoid arthritis (RA).Histologic studies were performed to compare the expression of CCR7 and CCL21 in RA synovial tissue. Next, the role of CCL21 and/or CCR7 in angiogenesis was examined using in vitro chemotaxis, tube formation, and in vivo Matrigel plug assays. Finally, the mechanism by which CCL21 mediates angiogenesis was determined by Western blot analysis and endothelial cell chemotaxis and tube formation assays.CCL21, but not CCL19, at concentrations present in the RA joint, induced human microvascular endothelial cell (HMVEC) migration that was mediated through CCR7 ligation. Suppression of the phosphatidylinositol 3-kinase pathway markedly reduced CCL21-induced HMVEC chemotaxis and tube formation; however, suppression of the ERK and JNK pathways had no effect on these processes. Neutralization of either CCL21 in RA synovial fluid or CCR7 in HMVECs significantly reduced the induction of HMVEC migration and/or tube formation by RA synovial fluid. We further demonstrated that CCL21 is angiogenic, by showing its ability to promote blood vessel growth in Matrigel plugs in vivo at concentrations that are present in RA joints.Angiogenesis is dependent on endothelial cell activation, migration, and proliferation, and inhibition of angiogenesis may provide a novel therapeutic approach in RA. This study identified a novel function of CCL21 as a mediator of RA angiogenesis, supporting CCL21/CCR7 as a therapeutic target in RA.
| S-EPMC3409328 | biostudies-literature
Project description:IntroductionAngiogenesis is an important process in the development of destructive synovial pannus in rheumatoid arthritis (RA). The ITGAV +gene encodes a cell cycle-associated antigen, integrin alphanubeta 3, which plays a role in RA angiogenesis. Previously, two independent studies identified an association between the major allele of the ITGAV single-nucleotide polymorphism (SNP) rs3738919 and RA. We therefore tested this association in an independent study using New Zealand (NZ) and Oxford (UK) RA case control samples.MethodsWe compared genotype frequencies in 740 NZ Caucasian RA patients and 553 controls genotyped for rs3738919, using a polymerase chain reaction-restriction fragment length polymorphism assay. A TaqMan genotyping SNP assay was used to type 713 Caucasian RA patients and 515 control samples from Oxford for the rs3738919 variant. Association of rs3738919 with RA was tested in these two sample sets using the chi-square goodness-of-fit test. The Mantel-Haenszel test was used to perform a meta-analysis, combining the genetic results from four independent Caucasian case control cohorts, consisting of 3,527 cases and 4,126 controls. Haplotype analysis was also performed using SNPs rs3911238, rs10174098 and rs3738919 in the Wellcome Trust Case Control Consortium, NZ and Oxford case control samples.ResultsWe found no evidence for association between ITGAV and RA in either the NZ or Oxford sample set (odds ratio [OR] = 0.88, P(allelic) = 0.11 and OR = 1.18, P(allelic) = 0.07, respectively). Inclusion of these data in a meta-analysis (random effects) of four independent cohorts (3,527 cases and 4,126 controls) weakens support for the hypothesis that rs3738919 plays a role in the development of RA (OR(combined) = 0.92, 95% confidence interval 0.80 to 1.07; P = 0.29). No consistent haplotype associations were evident.ConclusionsAssociation of ITGAV SNP rs7378919 with RA was not replicated in NZ or Oxford case control sample sets. Meta-analysis of these and previously published data lends limited support for a role for the ITGAV in RA in Caucasians of European ancestry.
| S-EPMC2787269 | biostudies-literature
Project description:The Wellcome Trust Case Control Consortium (WTCCC) identified nine single SNPs putatively associated with rheumatoid arthritis at P = 1 x 10(-5) - 5 x 10(-7) in a genome-wide association screen. One, rs6920220, was unequivocally replicated (trend P = 1.1 x 10(-8)) in a validation study, as described here. This SNP maps to 6q23, between the genes oligodendrocyte lineage transcription factor 3 (OLIG3) and tumor necrosis factor-alpha-induced protein 3 (TNFAIP3).
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Project description:The integrin alpha(v)beta3, whose alpha(v) subunit is encoded by the ITGAV gene, plays a key role in angiogenesis. Hyperangiogenesis is involved in rheumatoid arthritis (RA) and the ITGAV gene is located in 2q31, one of the suggested RA susceptibility loci. Our aim was to test the ITGAV gene for association and linkage to RA in a family-based study from the European Caucasian population. Two single nucleotide polymorphisms were genotyped by PCR-restriction fragment length polymorphism in 100 French Caucasian RA trio families (one RA patient and both parents), 100 other French families and 265 European families available for replication. The genetic analyses for association and linkage were performed using the comparison of allelic frequencies (affected family-based controls), the transmission disequilibrium test, and the genotype relative risk.We observed a significant RA association for the C allele of rs3738919 in the first sample (affected family-based controls, RA index cases 66.5% versus controls 56.7%; P = 0.04). The second sample showed the same trend, and the third sample again showed a significant RA association. When all sets were combined, the association was confirmed (affected family-based controls, RA index cases 64.6% versus controls 58.1%; P = 0.005). The rs3738919-C allele was also linked to RA (transmission disequilibrium test, 56.5% versus 50% of transmission; P = 0.009) and the C-allele-containing genotype was more frequent in RA index cases than in controls (RA index cases 372 versus controls 339; P = 0.002, odds ratio = 1.94, 95% confidence interval = 1.3-2.9). The rs3738919-C allele of the ITGAV gene is associated with RA in the European Caucasian population, suggesting ITGAV as a new minor RA susceptibility gene.
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Project description:Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by abnormal inflammation, angiogenesis, and cartilage destruction. In RA, neoangiogenesis is an early and crucial event to promote the formation of pannus, causing further inflammatory cell infiltration. The transcription factor GATA4 is a critical regulator of cardiac differentiation-specific gene expression. We find that a higher level of GATA4 exists in synovium of rheumatoid arthritis (RA) patients, but the function of GATA4 in RA remains unclear. In the present study, IL-1β induces inflammation in fibroblast-like synoviocytes (FLS) MH7A, which is accompanied with the increased expression of GATA4 and VEGF production. Through application of GATA4 loss-of-function assays, we confirm the requirement of GATA4 expression for inflammation induced by IL-1β in FLS. In addition, we demonstrate for the first time that GATA4 plays key roles in regulating VEGF secretion from RA FLS to promote cellular proliferation, induce cell migration, and angiogenic tube formation of endothelial cells. GATA4 induces the angiogenic factors VEGFA and VEGFC, by directly binding to the promoter and enhancing transcription. The knockdown of GATA4 attenuates the development of collagen-induced arthritis (CIA) and prevents RA-augmented angiogenesis in vivo, which are accompanied with decreased VEGF level. These results reveal a previously unrecognized function for GATA4 as a regulator of RA angiogenesis and we provide experimental data validating the therapeutic target of GATA4 in RA mice.
| S-EPMC5931571 | biostudies-literature
Project description:ObjectiveRA patients have an increased risk of cardiovascular (CV) disease, although the mechanisms are unclear. As RA and CV disease may be associated through lipid profiles, we examined whether single nucleotide polymorphisms (SNPs) associated with RA susceptibility were associated with low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglyceride (TG) levels in RA subjects.MethodsPatients (n = 763) enrolled in the Veterans Affairs RA registry who were not on hydroxymethylglutaryl-CoA reductase inhibitor were genotyped for human leukocyte antigen shared epitope (HLA-DRB1-SE) and SNPs in the following genes: CTLA-4 (cytotoxic T-lymphocyte antigen 4), IL-10, PTPN22 (protein tyrosine phosphatase, non-receptor type 22), REL (c-Rel), STAT4 (signal transducer and activator of transcription protein), TNF- and TRAF1 (TNF receptor-associated factor 1). Other covariates included patient characteristics (age, gender, race, smoking status, education, BMI, modified CharlsonDeyo comorbidity index), CV characteristics (hypertension, diabetes, alcohol abuse), pharmacologic exposures (MTX, anti-TNF, glucocorticoids) and RA severity/activity markers (RA disease duration, mean DAS, CRP, RF positivity, anti-CCP positivity). Multivariate linear regression was performed to determine the factors associated with LDL, HDL and TG levels.ResultsThe REL SNP rs9309331 homozygous minor allele was associated with higher LDL levels. Caucasian race and increasing BMI were associated with lower HDL. Factors associated with higher TG were diabetes, Caucasian race and higher BMI.ConclusionThe REL SNP rs9309331 was associated with LDL levels in our study. This association is a possible explanation of the increased risk of RA patients for CV disease and requires further inquiry.
| S-EPMC4023559 | biostudies-literature
Project description:Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by multi-articular, symmetrical and invasive arthritis resulting from immune system abnormalities involving T and B lymphocytes. Although significant progress has been made in the understanding of RA pathogenesis, the underlying mechanisms are not fully understood. Recent studies suggest that NLRP3 inflammasome, a regulator of inflammation, might play an important role in the development of RA. There have been increasing clinical and pre-clinical evidence showing the treatment of NLRP3/IL-1β in inflammatory diseases. To provide a foundation for the development of therapeutic strategies, we will briefly summarize the roles of NLRP3 inflammasome in RA and explore its potential clinical treatment.
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Project description:INTRODUCTION: Interleukin-34 (IL-34) is a recently defined cytokine, showing a functional overlap with macrophage colony stimulating factor (M-CSF). This study was undertaken to address the expression of IL-34 in rheumatoid arthritis (RA) patients and to investigate its regulation and pathogenic role in RA. METHODS: IL-34 levels were determined in the RA synovium, synovial fluid (SF) and fibroblast-like synovial cells (FLS) by immunohistochemistry, real-time PCR, enzyme-linked immunosorbent assay and immunoblotting. RA activity was assessed using Disease Activity Score 28 (DAS28) activity in the plasma collected at baseline and one year after treatment. Conditioned media (CM) were prepared from RA FLS culture with tumor necrosis factor alpha (TNF?) for 24 hours and used for functional assay. RESULTS: IL-34 was expressed in the synovium, SF, and FLS from RA patients. The production of IL-34 in FLS was up-regulated by TNF? in RA samples compared with osteoarthritis (OA) patients. Importantly, the preferential induction of IL-34 rather than M-CSF by TNF? in RAFLS was mediated by the transcription factor nuclear factor kappa B (NF-?B) and activation of c-Jun N-terminal kinase (JNK). IL-34 elevation in plasma from RA patients was decreased after the administration of disease-modifying anti-rheumatic drugs (DMARDs) in accordance with a decrease in DAS28. CM from RAFLS cultured with TNF? promoted chemotactic migration of human peripheral blood mononuclear cells (PBMCs) and subsequent osteoclast (OC) formation, effects that were attenuated by an anti-IL-34 antibody. CONCLUSIONS: These data provide novel information about the production of IL-34 in RA FLS and indicate that IL-34 is an additional osteoclastogenic factor regulated by TNF? in RA, suggesting a discrete role of IL-34 in inflammatory RA diseases.
| S-EPMC3392804 | biostudies-other