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Int. J. Mol. Sci. 2016, 17(9), 1389; doi:10.3390/ijms17091389

Hypoxia Suppresses Spontaneous Mineralization and Osteogenic Differentiation of Mesenchymal Stem Cells via IGFBP3 Up-Regulation

1
College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 21983, Korea
2
Stemore Co., Ltd., Incheon 21983, Korea
3
Department of Integrated OMICS for Biomedical Sciences, Yonsei University, Seoul 03722, Korea
4
Inha University School of Medicine, Translational Research Center and Inha Research, Institute for Medical Sciences, Incheon 21983, Korea
5
College of Pharmacy, Ajou University, Suwon 16499, Korea
6
Department of Dermatology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 03722, Korea
7
Department of Biochemistry, Stony Brook University, Stony Brook, NY 11790, USA
*
Authors to whom correspondence should be addressed.
Academic Editor: Gregor Drummen
Received: 23 June 2016 / Revised: 14 August 2016 / Accepted: 15 August 2016 / Published: 24 August 2016
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
View Full-Text   |   Download PDF [3240 KB, uploaded 24 August 2016]   |  

Abstract

Hypoxia has diverse stimulatory effects on human adipose-derived stem cells (ASCs). In the present study, we investigated whether hypoxic culture conditions (2% O2) suppress spontaneous mineralization and osteogenic differentiation of ASCs. We also investigated signaling pathways and molecular mechanisms involved in this process. We found that hypoxia suppressed spontaneous mineralization and osteogenic differentiation of ASCs, and up-regulated mRNA and protein expression of Insulin-like growth factor binding proteins (IGFBPs) in ASCs. Although treatment with recombinant IGFBPs did not affect osteogenic differentiation of ASCs, siRNA-mediated inhibition of IGFBP3 attenuated hypoxia-suppressed osteogenic differentiation of ASCs. In contrast, overexpression of IGFBP3 via lentiviral vectors inhibited ASC osteogenic differentiation. These results indicate that hypoxia suppresses spontaneous mineralization and osteogenic differentiation of ASCs via intracellular IGFBP3 up-regulation. We determined that reactive oxygen species (ROS) generation followed by activation of the MAPK and PI3K/Akt pathways play pivotal roles in IGFBP3 expression under hypoxia. For example, ROS scavengers and inhibitors for MAPK and PI3K/Akt pathways attenuated the hypoxia-induced IGFBP3 expression. Inhibition of Elk1 and NF-κB through siRNA transfection also led to down-regulation of IGFBP3 mRNA expression. We next addressed the proliferative potential of ASCs with overexpressed IGFBP3, but IGFBP3 overexpression reduced the proliferation of ASCs. In addition, hypoxia reduced the osteogenic differentiation of bone marrow-derived clonal mesenchymal stem cells. Collectively, our results indicate that hypoxia suppresses the osteogenic differentiation of mesenchymal stem cells via IGFBP3 up-regulation. View Full-Text
Keywords: adipose-derived stem cells; hypoxia; IGFBP3; reactive oxygen species; osteogenic differentiation adipose-derived stem cells; hypoxia; IGFBP3; reactive oxygen species; osteogenic differentiation
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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

Kim, J.H.; Yoon, S.M.; Song, S.U.; Park, S.G.; Kim, W.-S.; Park, I.G.; Lee, J.; Sung, J.-H. Hypoxia Suppresses Spontaneous Mineralization and Osteogenic Differentiation of Mesenchymal Stem Cells via IGFBP3 Up-Regulation. Int. J. Mol. Sci. 2016, 17, 1389.

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