Functional analysis of an arthritogenic synovial fibroblast.
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 extracellular 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.
Institute of Immunology, Biomedical Sciences Research Center Alexander Fleming, Athens, Greece. V.Aidinis@Fleming.gr
Vassilis
V
Aidinis
David
D
Plows
Sylva
S
Haralambous
Maria
M
Armaka
Petros
P
Papadopoulos
Maria Zambia
MZ
Kanaki
Dirk
D
Koczan
Hans Juergen
HJ
Thiesen
George
G
Kollias
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000473:pathology*; D001402:B-Lymphocytes / Q000502:physiology; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000473:pathology*; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000276:immunology; D016654:Genes, RAG-1 / Q000235:genetics; D006183:H-2 Antigens / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D013583:Synovial Membrane / Q000473:pathology*; D013601:T-Lymphocytes / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
D000276:Adjuvants, Immunologic; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D014409:Tumor Necrosis Factor-alpha