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The molecular pathogenesis of rheumatoid arthritis (RA) is still poorly understood and its clinical course can vary widely. In a recent report we noted heterogeneity in global gene expression signatures between synovial tissue specimens from different patients with RA. The results of the present study support the view that clinically diagnosed RA is a heterogeneous disease that is featured not only at the whole synovial tissue level but also at the level of FLS cultured from those tissues. One of the most impressive features of our 24k cDNA microarray profiling studies is the clear correlation of the FLS phenotype with that of paired synovial tissue from which the cells were derived. One class of FLS is tightly related to the presence of lymphocytes in the lesions whereas the other class of FLS suggests that synoviocyte-mediated invasion appears to be less dependent on infiltrating immune cells. Clearly, the list of genes that are differentially expressed between the FLS subgroups facilitates our understanding of the pathophysiology of the distinct groups of rheumatoid FLS. These data reveal features of fibrosis as the hallmark of FLS derived from a high inflammatory lesion, whereas FLS that are characterized by deregulated growth appear to constitute a characteristic feature of low inflammatory tissues. These data support the notion that heterogeneity between synovial tissues is reflected in the FLS as a stable trait and provide a molecular basis for the well recognized but as yet poorly understood heterogeneity in RA.