Activation of autophagy by FOXO3 regulates redox homeostasis during osteogenic differentiation

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Title: Activation of autophagy by FOXO3 regulates redox homeostasis during osteogenic differentiation
Author(s): Gómez-Puerto, MC
Verhagen, LP
Braat, AK
Lam, EWF
Coffer, PJ
Lorenowicz, MJ
Item Type: Journal Article
Abstract: Bone remodeling is a continuous physiological process that requires constant generation of new osteoblasts from mesenchymal stem cells (MSCs). Differentiation of MSCs to osteoblast requires a metabolic switch from glycolysis to increased mitochondrial respiration to ensure the sufficient energy supply to complete this process. As a consequence of this increased mitochondrial metabolism, the levels of endogenous reactive oxygen species (ROS) rise. In the current study we analyzed the role of forkhead box O3 (FOXO3) in the control of ROS levels in human MSCs (hMSCs) during osteogenic differentiation. Treatment of hMSCs with H2O2 induced FOXO3 phosphorylation at Ser294 and nuclear translocation. This ROS-mediated activation of FOXO3 was dependent on mitogen-activated protein kinase 8 (MAPK8/JNK) activity. Upon FOXO3 downregulation, osteoblastic differentiation was impaired and hMSCs lost their ability to control elevated ROS levels. Our results also demonstrate that in response to elevated ROS levels, FOXO3 induces autophagy in hMSCs. In line with this, impairment of autophagy by autophagy-related 7 (ATG7) knockdown resulted in a reduced capacity of hMSCs to regulate elevated ROS levels, together with a reduced osteoblast differentiation. Taken together our findings are consistent with a model where in hMSCs, FOXO3 is required to induce autophagy and thereby reduce elevated ROS levels resulting from the increased mitochondrial respiration during osteoblast differentiation. These new molecular insights provide an important contribution to our better understanding of bone physiology.
Publication Date: 17-Aug-2016
Date of Acceptance: 14-Jun-2016
ISSN: 1554-8635
Publisher: Taylor & Francis
Start Page: 1804
End Page: 1816
Journal / Book Title: Autophagy
Volume: 12
Issue: 10
Copyright Statement: © 2016 Taylor & Francis. "This is an Author's Accepted Manuscript of an article published in Autophagy, 17 August 2016, © Taylor & Francis, available online at:
Keywords: Biochemistry & Molecular Biology
0601 Biochemistry And Cell Biology
Publication Status: Published
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine

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