Karouzakis, E; Gay, R E; Gay, S; Neidhart, M (2012). Increased recycling of polyamines is associated with global DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis and Rheumatism, 64(6):1809-1817.
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OBJECTIVE: Global DNA hypomethylation in rheumatoid arthritis synovial fibroblasts (RASF) contributes to their intrinsic activation. The aim is to explore that an increased polyamine metabolism is associated with a decreased level of S-adenosylmethionine (SAM), causing the global DNA hypomethylation. METHODS: RASF (n = 12) and osteoarthritis synovial fibroblasts (OASF, n = 6) were isolated from synovial tissues. The cells were stained for adenosylmethionine decarboxylase (AMD), spermine/spermidine N1-acetyltransferase (SSAT1), polyamine modulated factor binding protein 1 (PMFBP1), solute carrier3A2 (SC3A2), DNA methyltransferase1 (Dnmt1), integrin α9, and β1, were analyzed by flow cytometry. Nuclear 5-methylcytosine (5-MeC) was measured by flow cytometry, diacetylspermine (DASp) in cell culture supernatants and cell extracts were determined by ELISA and SAM was measured in cell extracts by fluorometry. RESULTS: SSAT1, AMD and PMFBP1 were significantly (p < 0.05) increased in RASF, compared to OASF. DASp in cell culture supernatants and SC3A2 were significantly elevated (p < 0.01) in RASF. The levels of SAM in cell culture extracts, as well as of Dnmt1 protein and 5-MeC were significantly reduced (p < 0.001) in RASF. Parameters of the polyamines metabolism negatively correlated with SAM, Dnmt1 and 5-MeC. Supplementation of RASF with SAM increased Dnmt1 and 5-MeC, whereas integrin β1 was decreased. CONCLUSION: These data clearly show that intrinsic elevations of PMFBP1 and SSAT1 enhance the catabolism and recycling of polyamines in RASF and suggest that a high consumption of SAM by this pathway is an important factor contributing to the global DNA hypomethylation in these cells.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > University Hospital Zurich > Rheumatology Clinic and Institute of Physical Medicine|
04 Faculty of Medicine > Center for Integrative Human Physiology
|DDC:||570 Life sciences; biology|
610 Medicine & health
|Deposited On:||29 Jan 2012 12:06|
|Last Modified:||28 Nov 2013 00:16|
|Citations:||Web of Science®. Times cited: 8|
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