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FoxO proteins restrain osteoclastogenesis and bone resorption by attenuating H2O2 accumulation
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FoxO proteins restrain osteoclastogenesis and bone resorption by attenuating H2O2 accumulation
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Journal Article
FoxO proteins restrain osteoclastogenesis and bone resorption by attenuating H2O2 accumulation
2014
Overview
Besides their cell-damaging effects in the setting of oxidative stress, reactive oxygen species (ROS) play an important role in physiological intracellular signalling by triggering proliferation and survival. FoxO transcription factors counteract ROS generation by upregulating antioxidant enzymes. Here we show that intracellular H
2
O
2
accumulation is a critical and purposeful adaptation for the differentiation and survival of osteoclasts, the bone cells responsible for the resorption of mineralized bone matrix. Using mice with conditional loss or gain of FoxO transcription factor function, or mitochondria-targeted catalase in osteoclasts, we demonstrate this is achieved, at least in part, by downregulating the H
2
O
2
-inactivating enzyme catalase. Catalase downregulation results from the repression of the transcriptional activity of FoxO1, 3 and 4 by RANKL, the indispensable signal for the generation of osteoclasts, via an Akt-mediated mechanism. Notably, mitochondria-targeted catalase prevented the loss of bone caused by loss of oestrogens, suggesting that decreasing H
2
O
2
production in mitochondria may represent a rational pharmacotherapeutic approach to diseases with increased bone resorption.
Osteoclasts are bone-resorbing cells responsible for the loss of bone mass in diseases such as osteoporosis. Here the authors show that osteoclast proliferation and survival is regulated by FoxO family transcription factors, which control levels of the signalling molecule hydrogen peroxide.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Pub. Group
Subject
/ 13/106
/ 13/95
/ 38
/ 38/1
/ 38/77
/ 38/88
/ 59
/ 64
/ 64/60
/ 692/308
/ 96
/ Animals
/ Bone Resorption - physiopathology
/ Forkhead Transcription Factors - genetics
/ Forkhead Transcription Factors - metabolism
/ Gene Expression Regulation, Enzymologic - genetics
/ Gene Expression Regulation, Enzymologic - physiology
/ Humanities and Social Sciences
/ Hydrogen Peroxide - metabolism
/ Mice
/ Reactive Oxygen Species - metabolism
/ Real-Time Polymerase Chain Reaction
/ Science
