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Int. J. Mol. Sci. 2018, 19(1), 202; doi:10.3390/ijms19010202

Conditions Inducing Excessive O-GlcNAcylation Inhibit BMP2-Induced Osteogenic Differentiation of C2C12 Cells

1
Department of Molecular Genetics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 08826, Korea
2
Department of Pharmacology, College of Dentistry and Research Institute of Oral Science, Gangneung-Wonju National University, Chuncheon 25457, Gangwon-do, Korea
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 27 October 2017 / Revised: 3 January 2018 / Accepted: 5 January 2018 / Published: 9 January 2018
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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Abstract

Hyperglycemic conditions in diabetic patients can affect various cellular functions, including the modulation of osteogenic differentiation. However, the molecular mechanisms by which hyperglycemia affects osteogenic differentiation are yet to be clarified. This study aimed to investigate whether the aberrant increase in protein O-linked-β-N-acetylglucosamine glycosylation (O-GlcNAcylation) contributes to the suppression of osteogenic differentiation due to hyperglycemia. To induce osteogenic differentiation, C2C12 cells were cultured in the presence of recombinant human bone morphogenetic protein 2 (BMP2). Excessive protein O-GlcNAcylation was induced by treating C2C12 cells with high glucose, glucosamine, or N-acetylglucosamine concentrations or by O-GlcNAc transferase (OGT) overexpression. The effect of O-GlcNAcylation on osteoblast differentiation was then confirmed by examining the expression levels of osteogenic marker gene mRNAs, activity of alkaline phosphatase, and transcriptional activity of Runx2, a critical transcription factor for osteoblast differentiation and bone formation. Cell treatment with high glucose, glucosamine or N-acetylglucosamine increased O-GlcNAcylation of Runx2 and the total levels of O-GlcNAcylated proteins, which led to a decrease in the transcriptional activity of Runx2, expression levels of osteogenic marker genes (Runx2, osterix, alkaline phosphatase, and type I collagen), and activity of alkaline phosphatase. These inhibitory effects were rescued by lowering protein O-GlcNAcylation levels by adding STO45849, an OGT inhibitor, or by overexpressing β-N-acetylglucosaminidase. Our findings suggest that excessive protein O-GlcNAcylation contributes to high glucose-suppressed osteogenic differentiation. View Full-Text
Keywords: excessive O-GlcNAcylation; osteogenic differentiation; Runx2; hyperglycemia excessive O-GlcNAcylation; osteogenic differentiation; Runx2; hyperglycemia
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Gu, H.; Song, M.; Boonanantanasarn, K.; Baek, K.; Woo, K.M.; Ryoo, H.-M.; Baek, J.-H. Conditions Inducing Excessive O-GlcNAcylation Inhibit BMP2-Induced Osteogenic Differentiation of C2C12 Cells. Int. J. Mol. Sci. 2018, 19, 202.

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