The prognostic value of viral detection
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.
Key idea/result:
The inhibition of the PMF1 – SSAT1 axis is the first therapy that would directly target RASFs and thereby inhibit ongoing joint destruction.
Author:
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.