Akt1 in osteoblasts and osteoclasts controls bone remodeling.
Akt1 in osteoblasts and osteoclasts controls bone remodeling.
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DOI：
10.1371/journal.pone.0001058
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发表时间：
2007-10-24
期刊：
影响因子：
3.7
通讯作者：
Kawaguchi H
中科院分区：
文献类型：
--
作者：
Kawamura N;Kugimiya F;Oshima Y;Ohba S;Ikeda T;Saito T;Shinoda Y;Kawasaki Y;Ogata N;Hoshi K;Akiyama T;Chen WS;Hay N;Tobe K;Kadowaki T;Azuma Y;Tanaka S;Nakamura K;Chung UI;Kawaguchi H
骨量和骨更新是由成骨细胞的骨形成和破骨细胞的骨吸收之间的协调平衡维持的，受到许多全身和局部因素的调节。磷酸肌肽依赖丝氨酸-苏氨酸蛋白激酶Akt是骨合成代谢因子信号通路的关键参与者之一。本研究最初表明，小鼠成骨细胞和破骨细胞中Akt的主要蛋白Akt1的破坏通过两种细胞的功能障碍导致低周转率骨质减少。体外细胞培养分析显示，成骨细胞功能障碍可追溯到线粒体依赖性凋亡易感性增加和成骨细胞分化的主要调节因子runt相关转录因子2 （Runx2）的转录活性降低。值得注意的是，我们的研究结果揭示了Akt1/叉头盒类O (FoxO) 3a/Bim轴在成骨细胞凋亡中的新作用：Akt1磷酸化转录因子FoxO3a以阻止其核定位，导致其靶基因Bim的转激活受损，而Bim也被证明是成骨细胞中有效的促凋亡分子。破骨细胞功能障碍是由于破骨细胞分化和存活的细胞自主缺陷以及破骨细胞发生的主要决定因素核因子-κB受体激活因子配体（RANKL）在成骨细胞中的表达减少。Akt1通过促进成骨细胞和破骨细胞的分化和存活来维持骨量和骨转换，被认为是成骨细胞和破骨细胞的重要调节因子。本研究发现的分子网络将为骨疾病的合理治疗靶点提供依据。
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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FOXO转录因子直接激活BIM基因表达并促进交感神经元中的凋亡。
影响因子：
7.8
作者：
Gilley, Jonathan;Coffer, Paul J;Ham, Jonathan
通讯作者：
Ham, Jonathan
影响因子：
11.4
作者：
Akiyama, T;Bouillet, P;Tanaka, S
通讯作者：
Tanaka, S
影响因子：
10.5
作者：
Chen, WS;Xu, PZ;Hay, N
通讯作者：
Hay, N
DOI：
10.1073/pnas.0604153104
发表时间：
2007-02-13
影响因子：
11.1
作者：
Liu, Ximeng;Bruxvoort, Katia J.;Clemens, Thomas L.
通讯作者：
Clemens, Thomas L.
影响因子：
6.2
作者：
Jilka, RL;Weinstein, RS;Manolagas, SC
通讯作者：
Manolagas, SC