Akt regulates skeletal development through GSK3, mTOR, and FoxOs
Akt regulates skeletal development through GSK3, mTOR, and FoxOs
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DOI：
10.1016/j.ydbio.2009.01.009
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发表时间：
2009-04-01
影响因子：
2.7
通讯作者：
Komori, Toshihisa
中科院分区：
文献类型：
--
作者：
Rokutanda, Satoshi;Fujita, Takashi;Komori, Toshihisa
虽然Akt在各种细胞过程中发挥关键作用，但Akt及其下游信号通路在骨骼发育的细胞过程中的功能仍有待阐明。通过分析在软骨细胞中表达组成型活性Akt（myrAkt）或显性阴性Akt的转基因胚胎，我们发现Akt正调控软骨细胞成熟、软骨细胞增殖、软骨基质产生和骨骼发育中细胞生长的四个过程。由于在myrAkt转基因小鼠的生长板中GSK 3 β、S6 K和FoxO 3a的磷酸化增强，我们通过器官培养检测了Akt下游信号通路。Akt-mTOR通路负责这四种细胞过程的正调控。Akt-FoxO途径增强软骨细胞增殖，但抑制软骨细胞成熟和软骨基质产生，而Akt-GSK 3途径负调控肢体骨骼中的三个细胞过程，但由于椎骨中GSK 3表达较少，因此在椎骨中不调控。这些发现表明Akt正调控骨骼生长和软骨内骨化的细胞过程，Akt-mTOR、Akt-FoxO和Akt-GSK 3途径正或负调控细胞过程，并且Akt通过以依赖于骨骼部分的方式调节这三种途径来发挥其在骨骼发育中的功能。(C)2009 Elsevier Inc. All rights reserved.
Although Akt plays key roles in various cellular processes, the functions of Akt and Akt downstream signaling pathways in the cellular processes of skeletal development remain to be clarified. By analyzing transgenic embryos that expressed constitutively active Akt (myrAkt) or dominant-negative Akt in chondrocytes, we found that Akt positively regulated the four processes of chondrocyte maturation, chondrocyte proliferation, cartilage matrix production, and cell growth in skeletal development. As phosphorylation of GSK3 beta, S6K, and FoxO3a was enhanced in the growth plates of myrAkt transgenic mice, we examined the Akt downstream signaling pathways by organ culture. The Akt-mTOR pathway was responsible for positive regulation of the four cellular processes. The Akt-FoxO pathway enhanced chondrocyte proliferation but inhibited chondrocyte maturation and cartilage matrix production, while the Akt-GSK3 pathway negatively regulated three of the cellular Processes in limb skeletons but not in vertebrae due to less GSK3 expression in vertebrae. These findings indicate that Akt positively regulates the cellular processes of skeletal growth and endochondral ossification, that the Akt-mTOR, Akt-FoxO, and Akt-GSK3 pathways positively OF negatively regulate the cellular processes, and that Akt exerts its function in skeletal development by tuning the three pathways in a manner dependent on the skeletal part. (C) 2009 Elsevier Inc. All rights reserved.