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Arthritis Rheumatol. 2014 Jul;66(7):1723-33. doi: 10.1002/art.38574.

Inhibition of spermidine/spermine N1-acetyltransferase activity: a new therapeutic concept in rheumatoid arthritis.

Author information

1
Zurich Center of Integrative Human Physiology, Center of Experimental Rheumatology, and University Hospital Zurich, Zurich, Switzerland.

Abstract

OBJECTIVE:

Changes in polyamine-modulated factor 1 (PMF-1) promoter methylation might favor the expression of spermidine/spermine N1-acetyltransferase 1 (SSAT-1), causing excessive consumption of S-adenosyl methionine (SAM). This study was undertaken to evaluate the effect of SSAT-1 activity inhibition, either alone or in combination with SAM.

METHODS:

Synovial fibroblasts were isolated from patients with rheumatoid arthritis (RA) or osteoarthritis (OA). PMF-1 promoter methylation was determined by pyrosequencing. Small interfering RNAs (siRNAs) against SSAT-1 were transfected weekly in RA synovial fibroblasts (RASFs). In addition, synovial fibroblasts were treated with diminazene aceturate (DA), an inhibitor of SSAT-1. SSAT-1, 5-methylcytosine (5-MeC), adenosyl methionine decarboxylase (AMD), PMF-1, DNA methyltransferase 1 (DNMT-1), CXCL12, β1 integrin, and CD44 levels were measured by flow cytometry. Putrescine levels were determined by colorimetry. Levels of matrix metalloproteinases were measured by enzyme-linked immunosorbent assay. Cell adhesion was tested. The SCID mouse model of RA was used to monitor the invasiveness of RASFs.

RESULTS:

RASFs showed elevated SSAT-1, AMD, and PMF-1 levels. However, PMF-1 promoter methylation was unchanged. Transfection of siRNA targeting SSAT-1 increased 5-MeC levels within 21 days. Similarly, DA increased 5-MeC levels in RASFs. In addition, DA increased the levels of DNMT-1, decreased the levels of AMD, putrescine, activation markers, and MMP-1, and altered the adhesion of RASFs. DA was more efficient in RASFs with higher levels of SSAT-1. Most interestingly, the combination of DA and SAM reduced the invasiveness of RASFs by 70%.

CONCLUSION:

The use of DA alone or in combination with SAM/L-methionine might introduce a new therapeutic concept in RA. This is the first therapy that would directly target RASFs and thereby inhibit ongoing joint destruction.

PMID:
24578214
DOI:
10.1002/art.38574
[Indexed for MEDLINE]
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