Cargando…
Akt1 in Osteoblasts and Osteoclasts Controls Bone Remodeling
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2007
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2020440/ https://www.ncbi.nlm.nih.gov/pubmed/17957242 http://dx.doi.org/10.1371/journal.pone.0001058 |
_version_ | 1782136597059207168 |
---|---|
author | 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, Ung-il Kawaguchi, Hiroshi |
author_facet | 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, Ung-il Kawaguchi, Hiroshi |
author_sort | Kawamura, Naohiro |
collection | PubMed |
description | 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. |
format | Text |
id | pubmed-2020440 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2007 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-20204402007-10-24 Akt1 in Osteoblasts and Osteoclasts Controls Bone Remodeling 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, Ung-il Kawaguchi, Hiroshi PLoS One Research Article 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. Public Library of Science 2007-10-24 /pmc/articles/PMC2020440/ /pubmed/17957242 http://dx.doi.org/10.1371/journal.pone.0001058 Text en Kawamura et al. http://creativecommons.org/licenses/by/4.0/ 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 properly credited. |
spellingShingle | Research Article 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, Ung-il Kawaguchi, Hiroshi Akt1 in Osteoblasts and Osteoclasts Controls Bone Remodeling |
title | Akt1 in Osteoblasts and Osteoclasts Controls Bone Remodeling |
title_full | Akt1 in Osteoblasts and Osteoclasts Controls Bone Remodeling |
title_fullStr | Akt1 in Osteoblasts and Osteoclasts Controls Bone Remodeling |
title_full_unstemmed | Akt1 in Osteoblasts and Osteoclasts Controls Bone Remodeling |
title_short | Akt1 in Osteoblasts and Osteoclasts Controls Bone Remodeling |
title_sort | akt1 in osteoblasts and osteoclasts controls bone remodeling |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2020440/ https://www.ncbi.nlm.nih.gov/pubmed/17957242 http://dx.doi.org/10.1371/journal.pone.0001058 |
work_keys_str_mv | AT kawamuranaohiro akt1inosteoblastsandosteoclastscontrolsboneremodeling AT kugimiyafumitaka akt1inosteoblastsandosteoclastscontrolsboneremodeling AT oshimayasushi akt1inosteoblastsandosteoclastscontrolsboneremodeling AT ohbashinsuke akt1inosteoblastsandosteoclastscontrolsboneremodeling AT ikedatoshiyuki akt1inosteoblastsandosteoclastscontrolsboneremodeling AT saitotaku akt1inosteoblastsandosteoclastscontrolsboneremodeling AT shinodayusuke akt1inosteoblastsandosteoclastscontrolsboneremodeling AT kawasakiyosuke akt1inosteoblastsandosteoclastscontrolsboneremodeling AT ogatanaoshi akt1inosteoblastsandosteoclastscontrolsboneremodeling AT hoshikazuto akt1inosteoblastsandosteoclastscontrolsboneremodeling AT akiyamatoru akt1inosteoblastsandosteoclastscontrolsboneremodeling AT chenwilliams akt1inosteoblastsandosteoclastscontrolsboneremodeling AT haynissim akt1inosteoblastsandosteoclastscontrolsboneremodeling AT tobekazuyuki akt1inosteoblastsandosteoclastscontrolsboneremodeling AT kadowakitakashi akt1inosteoblastsandosteoclastscontrolsboneremodeling AT azumayoshiaki akt1inosteoblastsandosteoclastscontrolsboneremodeling AT tanakasakae akt1inosteoblastsandosteoclastscontrolsboneremodeling AT nakamurakozo akt1inosteoblastsandosteoclastscontrolsboneremodeling AT chungungil akt1inosteoblastsandosteoclastscontrolsboneremodeling AT kawaguchihiroshi akt1inosteoblastsandosteoclastscontrolsboneremodeling |