Lifelong accumulation of bone in mice lacking Pten in osteoblasts
Lifelong accumulation of bone in mice lacking Pten in osteoblasts
复制标题
DOI：
10.1073/pnas.0604153104
复制
发表时间：
2007-02-13
影响因子：
11.1
通讯作者：
Clemens, Thomas L.
中科院分区：
文献类型：
--
作者：
Liu, Ximeng;Bruxvoort, Katia J.;Clemens, Thomas L.
骨形成是由成骨细胞进行的，成骨细胞是一种间充质细胞，其寿命和活性受生长因子信号网络的调节。生长因子激活磷脂酰肌醇3-激酶（PI3K），通过激活Akt/PKB增强细胞存活并拮抗细胞凋亡。这一过程受到Pten磷酸酶的负调控，Pten磷酸酶抑制PI3K的活性。在本研究中，我们通过cre介导的重组有条件地破坏成骨细胞中的Pten基因，研究了Akt在骨中的激活作用。成骨细胞中缺乏Pten的小鼠大小正常，但骨密度在一生中表现出戏剧性和逐渐增加。缺乏Pten的体外成骨细胞分化速度比对照组快，凋亡显著减少，这与磷酸化Akt水平的显著升高和活化Akt下游信号通路的激活有关。这些发现支持这种肿瘤抑制基因在调节成骨细胞寿命中的关键作用，并可能解释携带PTEN种系突变的患者的骨骼异常。
Bone formation is carried out by the osteoblast, a mesenchymal cell whose lifespan and activity are regulated by growth factor signaling networks. Growth factors activate phosphatidylinositol 3-kinase (PI3K), which enhances cell survival and antagonizes apoptosis through activation of Akt/PKB. This process is negatively regulated by the Pten phosphatase, which inhibits the activity of PI3K. In this study, we investigated the effects of Akt activation in bone in vivo by conditionally disrupting the Pten gene in osteoblasts by using Cre-mediated recombination. Mice deficient in Pten in osteoblasts were of normal size but demonstrated a dramatic and progressively increasing bone mineral density throughout life. In vitro osteoblasts lacking Pten differentiated more rapidly than controls and exhibited greatly reduced apoptosis in association with markedly increased levels of phosphorylated Akt and activation of signaling pathways downstream of activated Akt. These findings support a critical role for this tumor-suppressor gene in regulating osteoblast lifespan and likely explain the skeletal abnormalities in patients carrying germ-line mutations of PTEN.