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 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-kappaB 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.
Kawamura
Naohiro
N
Department of Sensory and Motor System Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
Kugimiya
Fumitaka
F
Oshima
Yasushi
Y
Ohba
Shinsuke
S
Ikeda
Toshiyuki
T
Saito
Taku
T
Shinoda
Yusuke
Y
Kawasaki
Yosuke
Y
Ogata
Naoshi
N
Hoshi
Kazuto
K
Akiyama
Toru
T
Chen
William S
WS
Hay
Nissim
N
Tobe
Kazuyuki
K
Kadowaki
Takashi
T
Azuma
Yoshiaki
Y
Tanaka
Sakae
S
Nakamura
Kozo
K
Chung
Ung-il
UI
Kawaguchi
Hiroshi
H
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D016723:Bone Remodeling; D002454:Cell Differentiation; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D010006:Osteoblasts / Q000201:enzymology* / Q000378:metabolism; D010010:Osteoclasts / Q000201:enzymology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis*; D053245:RANK Ligand / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C467200:Foxo1 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D053245:RANK Ligand; D051057:Proto-Oncogene Proteins c-akt