Akt1 in Osteoblasts and Osteoclasts Controls Bone Remodeling
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Issue Date
2007-10-24Author
Kawamura, Naohiro
Kugimiya, Fumitaka
Oshima, Yasushi
Ohba, Shinsuke
Ikeda, Toshiyuki
Saito, Taku
Shinoda, Yusuke
Kawasaki, Yosuke
Ogata, Naoshi
Hoshi, Kazuto
Akiyama, Toru
Chen, William S.
Hay, Nissim
Tobe, Kazuyuki
Kadowaki, Takashi
Azuma, Yoshiaki
Tanaka, Sakae
Nakamura, Kozo
Chung, Ungil
Kawaguchi, Hiroshi
Publisher
Public Library of Science
Type
Article
Article Version
Scholarly/refereed, publisher version
Rights
©2007 Kawamura et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Show full item recordAbstract
Bone mass and turnover are maintained by the coordinated balance between bone formation by osteoblasts and bone resorption by osteoclasts, under regulation of many systemic and local factors. Phosphoinositide-dependent serine-threonine protein kinase Akt is one of the key players in the signaling of potent bone anabolic factors. This study initially showed that the disruption of Akt1, a major Akt in osteoblasts and osteoclasts, in mice led to low-turnover osteopenia through dysfunctions of both cells. Ex vivo cell culture analyses revealed that the osteoblast dysfunction was traced to the increased susceptibility to the mitochondria-dependent apoptosis and the decreased transcriptional activity of runt-related transcription factor 2 (Runx2), a master regulator of osteoblast differentiation. Notably, our findings revealed a novel role of Akt1/forkhead box class O (FoxO) 3a/Bim axis in the apoptosis of osteoblasts: Akt1 phosphorylates the transcription factor FoxO3a to prevent its nuclear localization, leading to impaired transactivation of its target gene Bim which was also shown to be a potent proapoptotic molecule in osteoblasts. The osteoclast dysfunction was attributed to the cell autonomous defects of differentiation and survival in osteoclasts and the decreased expression of receptor activator of nuclear factor-κB ligand (RANKL), a major determinant of osteoclastogenesis, in osteoblasts. Akt1 was established as a crucial regulator of osteoblasts and osteoclasts by promoting their differentiation and survival to maintain bone mass and turnover. The molecular network found in this study will provide a basis for rational therapeutic targets for bone disorders.
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- Pharmacy Scholarly Works [293]
Citation
Kawamura, N., Kugimiya, F., Oshima, Y., Ohba, S., Ikeda, T., Saito, T., … Kawaguchi, H. (2007). Akt1 in Osteoblasts and Osteoclasts Controls Bone Remodeling. PLoS ONE, 2(10). http://dx.doi.org/10.1371/journal.pone.0001058
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Except where otherwise noted, this item's license is described as: ©2007 Kawamura et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.