CULTURES OF FIBROBLAST-LIKE SYNOVIAL CELLS FROM PATIENTS WITH RHEUMATOID ARTHRITIS: PROPERTIES AND OPPORTUNITIES

The present review contains data from literature concerning the in vivo structure of synovial membranes in healthy people and patients with rheumatoid arthritis (RA). The properties of in vitro cultured fibroblast-like synovial cells (FLS) from RA patients are considered, including FLS morphology, phenotype and function. A standard protocol of in vitro FLS culturing is described. Notably, the FLS are characterized by autonomic functioning, ability for invasive growth/migration, e.g., into non-affected joints. These FLS properties may a reason of multiple joint involvement typical to RA. Special attention is drawn to characterization of stable phenotypic profile of FLS which results from certain epigenetic disturbances, i.e., changes of the DNA methylation, histone acetylation, and micro-RNA effects.

The FLS from RA patients are characterized with stable and extensive hypomethylation of genes which occurs in vivo and persists after repeated culture passages. Some promoters of genes involved into RA pathogenesis (for example, CXCL12, IL-6) are hypomethylated. By contrary, some other gene promoters (e.g., the death receptor 3 gene) are shown to be hypermethylated. An increased histone acetylation of genes encoding proinflammatory mediators (such as MMP1) may be an important mechanism of persistent inflammation in RA. Changes in histone acetylation in FLS are related to high levels of ubiquitin-like SUMO-1 protein and concurrent decrease in specific protease SENP1activity. A role of histone acetylation in RA pathogenesis is supported by efficacy of a histone deacetylase inhibitor (Trichostatin A) in collagen-induced murine arthritis. Local concentrations of micro RNA-155, micro-RNA-146а, and micro-RNA-203 are permanently increased in FLS cultures, synovial tissues, and PBMC of the RA patients. Expression of micro RNA-124а is decreased in FLS from RA, as compared with OA FLS.

One may conclude that the fibroblast-like synovial cells are key cellular elements involved in the pathogenesis of rheumatoid arthritis, and the studies of their impaired epigenetic regulation are at their initial stage. Enzymes and molecular complexes involved in these processes may represent potential therapeutic targets for the treatment of RA.

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