Sustained and Distinctive Patterns of Gene Activation in Synovial Fibroblasts and Whole Synovial Tissue Obtained from Inflammatory Synovitis

Abstract

Fibroblastoid synovial lining cells isolated from rheumatoid and other chronic inflammatory synovial tissue exhibit distinctive and sustained alterations in serial culture not commonly found in similarly cultured cells from osteoarthritic synovium. These are demonstrable using a multi-gene dot blot assay by labelling reverse transcribed fibroblast cDNA which is hybridized to plasmids containing relevant target gene inserts. Cultured synovial fibroblastoid cells from patients with chronic inflammatory synovitis expressed significantly higher levels of stromelysin, vimentin and TIMP-1 mRNA and lower levels of c-myc compared to cells isolated from osteoarthritis synovium although with considerable variation. Early fetal synovial lining cells were similar to cells from osteoarthritis synovium but vimentin expression was higher. Marked differences in patterns of gene expression between cell lines persisted through 10 serial passages over 6–8 months. In whole synovia, the average level of mRNA for stromelysin, vimentin, IL-4, IL-6, TIMP-1, cathepsin D, gelatinase, TGFα, c-fms and DRβ were preferentially expressed in inflammatory tissue while c-myc expression was higher in osteoarthritis synovium. Inflammatory synovium also expressed TNFα, IL-1α, IL-1β, IL-2, c-sis, tissue plasminogen activator, CSF-1, and GM-CSF. This pattern resembles, in part, that found in cultured inflammatory fibroblasts but, in addition., gene products apparently reflecting the presence of activated monocytes and lymphocytes were detected. These results provide evidence that profiles of certain gene activation in cells from patients with inflammatory synovitis differ from those with non-inflammatory disease and suggest that the fibroblastoid cells are responsible for a considerable proportion of the altered phenotypic expression pattern in whole tissue. Furthermore, this modulated pattern of gene activation appears to be an intrinsic pro-inflammatory characteristic of the fibroblastoid cells initiated in response to chronic inflammation and persists for a prolonged period in the absence of other inflammatory cells.