Disrupting bistability in rheumatoid arthritis synovial fibroblasts
RASF are the effector cells of joint destruction. They showed an intrinsically activated phenotype, releasing chemokines and matrix-degrading enzymes. No therapy directly targets these cells yet. RASF are characterized by epigenetic dysfunctions, in particular global DNA hypomethylation. Among other genes, this affects LINE-1, CXCL12 (a chemokine) and TBX5 (a transcription factor) promoters. in presence of pro-inflammatory cytokines or growth factors. Upon proliferation stimuli, RASF up-regulate less DNA methyltransferase 1 (DNMT1) than healthy fibroblasts, this contributes to a progressive global DNA demethylation. RASF have lower intracellular levels of S-adenosylmethyionine (SAM), the cell's methyl donor. An activated polyamine recycling pathway consumes SAM. Spermidine / spermine N1 acethyltransferase (SSAT1) is intrinsically upregulated. This is accompanied by high expression of polyamine modulating factor 1 (PMF1), which triggers the transcription of SSAT1. The current working hypothesis is that a positive feedback loop is established in RASF between DNA hypomethylation and increased levels of PMF1, leading to bistability, i.e. in an emerging stable pathological phenotype. RASF pretreated for two weeks with methyl donors (L-methionine or SAM) and/or an inhibitor of SSAT1 activity showed reduced aggressiveness. Methyl donors were not efficient in RASF cultures responding to SSAT1 inhibition. Thus, a new strategy would be to disrupt the positive feedback loop between DNA hypomethylation and activation of the polyamine back-conversion, at levels of SSAT1 itself or upstream of this enzyme. This concept is investigated using different approaches, pharmaceutical and molecular. Inhibition of SSAT1 or PMF1 activity and/or of its hypothetical upstream signaling might affect RASF phenotype. A possibility is also to disrupt the PMF1 / NrF2 interaction. Taken together, by targeting directly the effector cells of joint destruction, this project would lead to novel therapeutic strategies.
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