Inhibition of spermidine/spermine N1-acetyltransferase activity: a new therapeutic concept in rheumatoid arthritis.ocessesn
Inhibition of spermidine/spermine N1-acetyltransferase activity: a new therapeutic concept in rheumatoid arthritis.
Neidhart M, Karouzakis E, Jüngel A, Gay RE, Gay S.
Rheumatoid arthritis synovial fibroblasts (RASF) are characterized by a global DNA hypomethylation, in addition to hypo- or hypermethylation of specific promoters. Upon proliferation stimuli, RASF up-regulate less DNA methyltransferase 1 (DNMT1) than normal cells. In addition, they have lower intracellular levels of S-adenosylmethionine (SAM), the cell’s methyl donor. This results in a progressive DNA demethylation. Hypothesized was that a metabolic pathway consumes SAM, lowering its availability for DNMTs. Indeed, an intrinsic up-regulation of the polyamine back-conversion pathway, specifically of polyamine modulating factor 1 (PMF1) and spermine / spermidine N1-acethyltransferase (SSAT1), occurs in about half of the cases. Supplementation of these cells with methyl donors reduced their aggressiveness only after inhibition of SSAT1. The co-treatment particularly increases the level of DNMT1 and reduced the expression of matrix-degrading enzymes.
The inhibition of the PMF1 – SSAT1 axis is the first therapy that would directly target RASFs and thereby inhibit ongoing joint destruction.
Michel Neidhart is professor for experimental rheumatology and senior scientist at the Centre of Experimental Rheumatology, University Hospital Zurich. His interests are the epigenetic modifications in RASF and RA monocytes.
- Synovial fibroblasts