Potential mechanisms for coordinate gene activation in the rheumatoid synoviocyte: Implications and hypotheses

Abstract

Evidence is reviewed to support the concept that synovial cells in rheumatoid arthritis have undergone distinctive alterations at the cellular and subcellular level that result in their taking on some of the characteristics that are also manifest by transformed cells. These phenotypic modulations could be indirectly driven by cytokines in a paracrine or autocrine fashion. Specific regional patterns of cell phenotype modulation were used to argue against a simple widely diffusing direct inductive effect to cytokines and in favor of microenvironmental determinants. It is hypothesized that these extracellular factors induce novel activation in a coordinate manner by acting through master regulatory genes operating in cells with specific microenvironmental interactions. Two of these regulatory genes, fos and jun, are discussed in detail because of their induction by growth factors and their central role in the transactivation of genes which have been implicated in rheumatoid synovitis. A model for gene activation in the rheumatoid synovium is proposed based on the premise that fos and jun are an important link in the intracellular transduction pathways used by cytokines to induce cellular phenotypic changes.

Use of a differential subtraction method to identify genes that characterize the phenotype of cultured rheumatoid arthritis synoviocytes

“…These cell lines have been used to gain insight into the biology of joint inflammation (15)(16)(17)(18)(19)(20)(21)(22), although the origin of the cells in culture is somewhat uncertain and the types of cells found, at least at the time of culture initiation, include hyperplastic intimal synoviocytes, subintimal synoviocytes, other fibroblastoid cells, and non-mesenchymal cells that do not survive after 3 passages. We and others have postulated that the distinctive changcs in synoviocyte phenotype observed in these cell lines mirror certain similar events that occur in the inflamed synovium itself (14,15,(23)(24)(25).…”

Isolation and characterization of rheumatoid arthritis synovial fibroblasts from primary culture — primary culture cells markedly differ from fourth-passage cells

“…With culture times as short as 7 days, fresh SFB express surface and intracellular antigens typical of the FB lineage and/or SFB features as reported at a tissue level (Fig. 6 and Table 4) [1,2,12,13,14,15, 21,22,23,24,25,28]. This approach may also reduce the risk of in vitro growth selection.…”

Basic FGF-induced activation of telomerase in rheumatoid synoviocytes

“…The above studies suggest that the pathway encompassing autonomous proliferation of synoviocytes plays a pivotal role in synovial hyperplasia in RA [4,8]. Indeed, the synovium of RA is described morphologically as``tumor-like'' tissue, and synoviocytes exhibit the characteristics of transformed cells [9]. Moreover, synoviocytes with a strong proliferative activity, termed pannocytes, are also highly responsible for the bone and cartilage destruction and formation of pannus lesions [10].…”