Our data suggest that the VEGF gene may play a role in the development of RA

The chemokine receptor [C-C chemokine receptor 5 (CCR5)] is expressed on diverse immune effecter cells and has been implicated in the pathogenesis of rheumatoid arthritis (RA). This study sought to determine whether single-nucleotide polymorphisms (SNPs) in the CCR5 gene and their haplotypes were associated with susceptibility to and severity of RA. Three hundred fifty-seven patients with RA and 383 healthy unrelated controls were recruited. Using a pyrosequencing assay, we examined four polymorphisms -1118 CTAT(ins) (/del) (rs10577983), 303 A>G (rs1799987), 927 C>T (rs1800024), and 4838 G>T (rs1800874) of the CCR5 gene, which were distributed over the promoter region as well as the 5' and 3' untranslated regions. No significant difference in the genotype, allele, and haplotype frequencies of the four selected SNPs was observed between RA patients and controls. CCR5 polymorphisms of -1118 CTAT(del) (P = 0.012; corrected P = 0.048) and 303 A>G (P = 0.012; corrected P = 0.048) showed a significant association with radiographic severity in a recessive model, and, as a result of multivariate logistic regression analysis, were found to be an independent predictor of radiographic severity. When we separated the erosion score from the total Sharp score, the statistical significance of CCR5 polymorphisms showed an increase; -1118 CTAT(ins) (/del) (P = 0.007; corrected P = 0.028) and 303 A>G (P = 0.007; corrected P = 0.028). Neither SNPs nor haplotypes of the CCR5 gene showed a significant association with joint space narrowing score. These results indicate that genetic polymorphisms of CCR5 are an independent risk factor for radiographic severity denoted by modified Sharp score, particularly joint erosion in RA.

Background:Aggressiveness of synoviocytes and collective migration of organized synovial tissues play a key role in the pathogenesis of pannus invasion into adjacent joint structure. Interactions among synovial cells for grouped movement, however, have not been properly elucidated.Objectives:We hypothesized that cadherins which have functions on the synovial invasion in RA, may play a critical role in collective migration of rheumatoid synoviocytes.Methods:Cadherins expression patterns on the synoviocytes isolated from patients with RA were evaluated using RT-PCR, flow cytometry, and western blot analysis. Mesenchymal and epithelial phenotypes were examined in cadherin overexpressing cell line by flow cytometry. L-cells with overexpression of CDH2 (CDH2hi), CDH11 (CDH11hi), and combination of CDH2/CDH11 (CDH2hi/CDH11hi) were prepared. Migration of cells was observed by taking time-lapse images with laser confocal microscope.In vitrocollective migration and directional movement in response to inflammatory mediators and different matrix rigidity were evaluated.In vivohoming of CDH2hi/CDH11hi-L-cells into joint tissues was performed in collagen induced arthritis (CIA) mouse. In vivoandex vivomigration pattern of CDH11hi-L-cells were investigated in nude mice using optical imaging system.Results:In rheumatoid synovial tissues, CDH2 and CDH11 were highly expressed compared to synovial tissues from osteoarthritis. CDH2 and CDH11 were also highly expressed on synovial fibroblasts isolated from RA. Phenotype analysis of mesenchymal and epithelial cells in CDH11hi-L-cells and CDH2hi/CDH11hi-L-cells showed increased expression of α5β1, CD44s, vimentin, and α-SMA compared with MOCK-L-cells. We then analyzed the pattern of migration of MOCK, CDH2hi, CDH11hi, and CDH2hi/CDH11hi-L-cells using time lapse images. During migration over a hard ECM, CDH2hiand CDH11hi-L cells represented higher aspect ratio compare to a soft ECM. Aspect ratio relatively found lower in CDH2hi/CDH11hi-L-cell lines than MOCK cells. CDH2hi/CDH11hi-L-cells showed significantly higher migration velocity and Euclidean distance with narrower angle of migratory directions in a cytokine mediated migration. Compared to the MOCK cells, persistence ratio and aspect ratio of migration were also higher in CDH2hi, CDH11hi, and CDH2hi/CDH11hi-L-cells. CDH2hi/CDH11hi-L-cells collectively migrated with the formation of leader and follower cells. In a chemokine mediated hard stiffness of ECM, durotaxis was observed in CDH11hi-L-cells. After 24 hours of intraarticular knee injection in CIA mouse, higher number of CDH2hi/CDH11hi-L-cells invaded into the cartilage than MOCK cells.In vivomigration of CDH2hi/CDH11hi-L-cells was also found towards the chemokine and cartilage mixed matrigel plug in the subcutaneous space of mice.Conclusion:The expression of CDH2 and CDH11 promotes directional migration of synoviocytes, indicating the potential role of these cadherins on the pannus tissues in the invasion into adjacent joint structure in RA.References:[1]Noss EH, Chang SK, Watts GFM, Brenner MB. Cadherin-11 engagement modulates matrix metalloproteinase production by rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 2011 Dec; 63(12): 3768–3778Disclosure of Interests:None declared