Inhibition of methylation decreases osteoblast differentiation via a non-DNA-dependent methylation mechanism

Vaes, Bart L T, Lute, Carolien, van der Woning, Sebastian P, Piek, Ester, Vermeer, Jenny, Blom, Henk J, Mathers, John C, Müller, Michael, de Groot, Lisette C P G M and Steegenga, Wilma T (2010) Inhibition of methylation decreases osteoblast differentiation via a non-DNA-dependent methylation mechanism. Bone, 46 (2). pp. 514-523. ISSN 8756-3282

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Abstract

S-adenosylmethionine (SAM)-dependent methylation of biological molecules including DNA and proteins is rapidly being uncovered as a critical mechanism for regulation of cellular processes. We investigated the effects of reduced SAM-dependent methylation on osteoblast differentiation by using periodate oxidized adenosine (ADOX), an inhibitor of SAM-dependent methyltransferases. The capacity of this agent to modulate osteoblast differentiation was analyzed under non-osteogenic control conditions and during growth factor-induced differentiation and compared with the effect of inhibition of DNA methylation by 5-Aza-2'-deoxycytidine (5-Aza-CdR). Without applying specific osteogenic triggers, both ADOX and 5-Aza-CdR induced mRNA expression of the osteoblast markers Alp, Osx, and Ocn in murine C2C12 cells. Under osteogenic conditions, ADOX inhibited differentiation of both human mesenchymal stem cells and C2C12 cells. Gene expression analysis of early (Msx2, Dlx5, Runx2) and late (Alp, Osx, Ocn) osteoblast markers during bone morphogenetic protein 2-induced C2C12 osteoblast differentiation revealed that ADOX only reduced expression of the late phase Runx2 target genes. By using a Runx2-responsive luciferase reporter (6xOSE), we showed that ADOX reduced the activity of Runx2, while 5-Aza-CdR had no effect. Taken together, our data suggest that decreased SAM-dependent methyltransferase activity leads to impaired osteoblast differentiation via non-DNA-dependent methylation mechanisms and that methylation is a regulator of Runx2-controlled gene expression.

Item Type: Article
Additional Information: (c) 2009 Elsevier Inc. All rights reserved.
Uncontrolled Keywords: adenosine,alkaline phosphatase,animals,azacitidine,cell differentiation,cell line,core binding factor alpha 1 subunit,dna methylation,humans,mice,organ specificity,osteoblasts,osteogenesis,transcriptional activation
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Pure Connector
Date Deposited: 10 Jun 2014 21:36
Last Modified: 14 Sep 2020 07:04
URI: https://ueaeprints.uea.ac.uk/id/eprint/47695
DOI: 10.1016/j.bone.2009.09.033

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