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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-25517

Karouzakis, E; Gay, S; Michel, B A; Gay, R E; Neidhart, M (2009). DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis and Rheumatism, 60(12):3613-3622.

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Abstract

OBJECTIVE: Rheumatoid arthritis synovial fibroblasts (RASFs) are phenotypically activated and aggressive. We undertook this study to investigate whether the intrinsic activation of RASFs is due to global genomic hypomethylation, an epigenetic modification. METHODS: Global genomic hypomethylation was assessed by immunohistochemistry, flow cytometry, and L1 promoter bisulfite sequencing. The levels of Dnmt1 were determined in synovial tissue and cultured SFs by Western blotting before and after treatment with cytokines and growth factors. Normal SFs were treated for 3 months with a nontoxic dose of the DNA hypomethylation drug 5-azacytidine (5-azaC), and changes in gene expression were revealed using complementary DNA arrays. The phenotypic changes were confirmed by flow cytometry. RESULTS: In situ and in vitro, RASF DNA had fewer 5-methylcytosine and methylated CG sites upstream of an L1 open-reading frame than did DNA of osteoarthritis SFs, and proliferating RASFs were deficient in Dnmt1. Using 5-azaC, we reproduced the activated phenotype of RASFs in normal SFs. One hundred eighty-six genes were up-regulated >2-fold by hypomethylation, with enhanced protein expression. These included growth factors and receptors, extracellular matrix proteins, adhesion molecules, and matrix-degrading enzymes. The hypomethylating milieu induced irreversible phenotypic changes in normal SFs, which resembled those of the activated phenotype of RASFs. CONCLUSION: DNA hypomethylation contributes to the chronicity of RA and could be responsible for the limitation of current therapies.

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Integrative Human Physiology
04 Faculty of Medicine > University Hospital Zurich > Rheumatology Clinic and Institute of Physical Medicine
DDC:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2009
Deposited On:14 Dec 2009 10:44
Last Modified:27 Nov 2013 21:13
Publisher:Wiley-Liss / American College of Rheumatology
ISSN:0004-3591 (P) 1529-0131 (E)
Additional Information:The definitive version is available at www.blackwell-synergy.com
Publisher DOI:10.1002/art.25018
Official URL:http://www3.interscience.wiley.com/journal/123194943/abstract
PubMed ID:19950268
Citations:Web of Science®. Times Cited: 54
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