Liu Ximeng, Bruxvoort Katia J, Zylstra Cassandra R, Liu Jiarong, Cichowski Rachel, Faugere Marie-Claude, Bouxsein Mary L, Wan Chao, Williams Bart O, Clemens Thomas L
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Proc Natl Acad Sci U S A. 2007 Feb 13;104(7):2259-64. doi: 10.1073/pnas.0604153104. Epub 2007 Feb 7.
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.
骨形成由成骨细胞完成，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调控。生长因子激活磷脂酰肌醇3激酶（PI3K），PI3K通过激活Akt/PKB增强细胞存活并拮抗细胞凋亡。该过程受Pten磷酸酶负调控，Pten磷酸酶抑制PI3K的活性。在本研究中，我们通过利用Cre介导的重组条件性破坏成骨细胞中的Pten基因，研究了体内Akt激活对骨的影响。成骨细胞中缺乏Pten的小鼠体型正常，但在整个生命过程中骨矿物质密度显著且逐渐增加。体外实验中，缺乏Pten的成骨细胞比对照细胞分化更快，凋亡大大减少，同时磷酸化Akt水平显著升高，且Akt激活下游的信号通路也被激活。这些发现支持了这个肿瘤抑制基因在调节成骨细胞寿命方面的关键作用，并且可能解释了携带PTEN种系突变的患者的骨骼异常情况。
