Abstract
In rheumatoid arthritis (RA), an excess of proteolytic enzymes secreted at the synovium-cartilage junction results in the invasion of the articular cartilage by synovial cells. The aims of the present study were to investigate the effects of overexpression of TIMP-1 and TIMP-3 on: 1) the invasive behaviour of rheumatoid fibroblasts-like synoviocytes and 2) cell proliferation and apoptosis. The day before the experiments, the synoviocytes were infected with adenoviral vectors encoding TIMP-1 or TIMP-3 or with a control vector (AdLacZ). A Transwell system was used to study invasion of the cells. After 3 days, the invaded cells were counted using a microscope. Proliferation was assessed by measuring 3H-thymidine incorporation and cell counting. Apoptosis was assessed at 1-4 days after transduction using an Annexin V-FITC kit. Both TIMP-1 and TIMP-3 overexpression resulted in a significant reduction, respectively 60% (P < 0.001) and 80% (P < 0.001), of invasiveness of the synoviocytes as compared to the AdLacZ-transduced cells. In all cases, TIMP-3 was superior to TIMP-1 (P = 0.02). Cell proliferation was significantly reduced by TIMP-3 overexpression (40%; P < 0.05) and to a lesser extend by TIMP-1 (20%; P < 0.05) as compared to AdLacZ. There were little differences in % of apoptotic cells between the non-transduced, AdTIMP-1, AdTIMP-3 or Ad LacZ transduced cells up to 4 days after transduction. A maximum of 15% of the AdTIMP-3 transduced cells were in apoptotis as compared to a maximum of 12% in the other conditions. These results show that the invasive behavior of RA-FLSs can be strongly inhibited by overexpression of TIMPs. Both MMP inhibition and a reduction of proliferation appear to contribute to this effect. The superior effect of TIMP-3 may be due to a stronger effect on proliferation or to differences in the inhibitory profile of TIMP-1 and TIMP-3. To limit joint destruction in rheumatoid arthritis, inhibition of cartilage invasion by the pannus tissue by TIMP overexpression may be a useful approach.
Highlights
The presence of autoantibodies directed to citrullinated antigens in serum is highly specific for rheumatoid arthritis (RA)
We discuss the presence of anti-keratin antibodies (AKA) of the IgG class in patients with defined juvenile idiopathic arthritis (JIA)
Our study revealed that AKA was present overall in 18/29 patients (62%) with severe JIA and in 12/26 patients (46,2 %) with non-severe disease, this did not reach statistical significance (P = 0,18)
Summary
The presence of autoantibodies directed to citrullinated antigens in serum is highly specific for RA. Anti-CCP concentrations (expressed in Units per mg total IgG) were on average 1.34 times higher in SF compared to serum (n = 20, P < 0.05) or 1.37 when only positive samples were included (n = 11, P < 0.05) Conclusion: Citrullinated antigens are present in the synovia of both RA and control patients with similar prevalence. At higher concentrations (>1ng/μl) of RNA-oligonucleotides unspecific hybridization-signals prevailed in tissues of all diseases (even in normal controls) The combination of both methods (in situ-hybridization and immunohistochemistry) identifies the single cells inside the synovial lining layer which contains the highly expressed RAB3 “Kreisler” (maf B) gene. Conclusions: These data demonstrates for the first time that statins (and fluvastatin) are able to inhibit an endothelial proadhesive and pro-inflammatory phenotype induced by different stimuli including anti-β2GPI antibodies or pro-inflammatory cytokines These findings suggest a potential usefulness for statins in the prevention of the APS pro-atherothrombotic state
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