Institution: | (1) Institute of Immunology, Biomedical Sciences Research Center 'Alexander Fleming', Athens, Greece;(2) Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece;(3) Institute of Immunology, University of Rostock, Rostock, Germany |
Abstract: | Increasing attention has been directed towards identifying non-T-cell mechanisms as potential therapeutic targets in rheumatoid
arthritis. Synovial fibroblast (SF) activation, a hallmark of rheumatoid arthritis, results in inappropriate production of
chemokines and matrix components, which in turn lead to bone and cartilage destruction. We have demonstrated that SFs have
an autonomous pathogenic role in the development of the disease, by showing that they have the capacity to migrate throughout
the body and cause pathology specifically to the joints. In order to decipher the pathogenic mechanisms that govern SF activation
and pathogenic potential, we used the two most prominent methods of differential gene expression analysis, differential display
and DNA microarrays, in a search for deregulated cellular pathways in the arthritogenic SF. Functional clustering of differentially
expressed genes, validated by dedicated in vitro functional assays, implicated a number of cellular pathways in SF activation. Among them, diminished adhesion to the extracellullar
matrix was shown to correlate with increased proliferation and migration to this matrix. Our findings support an aggressive
role for the SF in the development of the disease and reinforce the perspective of a transformed-like character of the SF. |