Activation of autophagy by FOXO3 regulates redox homeostasis during osteogenic differentiation
File(s)
Accepted version
Author(s)
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.
Date Issued
2016-08-17
Date Acceptance
2016-06-14
Citation
Autophagy, 2016, 12 (10), pp.1804-1816
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: http://www.tandfonline.com/10.1080/15548627.2016.1203484.
Subjects
Biochemistry & Molecular Biology
0601 Biochemistry And Cell Biology
Publication Status
Published