Activating transcription factor 4 is critical for proliferation and survival in primary bone marrow stromal cells and calvarial osteoblasts.
Activating transcription factor 4 is critical for proliferation and survival in primary bone marrow stromal cells and calvarial osteoblasts.
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DOI：
10.1002/jcb.21888
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发表时间：
2008-10-15
影响因子：
4
通讯作者：
Xiao, Guozhi
中科院分区：
文献类型：
--
作者：
Zhang, Xiaoyan;Yu, Shibing;Galson, Deborah L.;Luo, Min;Fan, Jie;Zhang, Jian;Guan, Youfei;Xiao, Guozhi
转录激活因子4（ATF 4）是骨形成所必需的。然而，其在骨中的作用机制知之甚少。本研究探讨了ATF 4在调节原代小鼠骨髓基质细胞和成骨细胞增殖和存活中的作用。结果表明，Atf 4 −/−细胞显示出严重的增殖缺陷，如通过多种细胞增殖测定所测量的。Atf 4 −/− BMSCs的细胞周期进程在很大程度上延迟，并出现显著的G1期阻滞。细胞周期蛋白D1在mRNA和蛋白水平的表达均降低。与野生型对照相比，在Atf 4 −/−颅骨骨膜成骨细胞中观察到类似的增殖缺陷。在MC 3 T3-E1亚克隆4前成骨细胞中，用小干扰RNA敲低Atf 4 mRNA可显著降低细胞周期蛋白D1的表达和细胞增殖。相反，ATF 4的过表达增加了Atf 4 −/− BMSCs中细胞周期蛋白D1的表达以及细胞增殖。此外，相对于野生型对照，Atf 4 −/− BMSCs和颅骨骨膜成骨细胞的凋亡显著增加。综上所述，这些结果首次证明，ATF 4是体外和体内BMSC和成骨细胞增殖和存活的关键调节因子。
Activating transcription factor 4 (ATF4) is essential for bone formation. However, the mechanism of its actions in bone is poorly understood. The present study examined the role for ATF4 in the regulation of proliferation and survival of primary mouse bone marrow stromal cells (BMSCs) and osteoblasts. Results showed that Atf4−/− cells display a severe proliferative defect as measured by multiple cell proliferation assays. Cell cycle progression of Atf4−/− BMSCs was largely delayed with significant G1 arrest. Expression of cyclin D1 was decreased both at the mRNA and protein level. A similar proliferation defect was observed in Atf4−/− calvarial periosteal osteoblasts when compared with wt control. Knocking down Atf4 mRNA by small interfering RNA in MC3T3-E1 subclone 4 preosteoblasts markedly reduced expression of cyclin D1 and cell proliferation. In contrast, overexpression of ATF4 increased cyclin D1 expression as well as cell proliferation in Atf4−/− BMSCs. In addition, apoptosis was significantly increased in Atf4−/− BMSCs and calvarial periosteal osteoblasts relative to wt controls. Taken together, these results for the first time demonstrate that ATF4 is a critical regulator of proliferation and survival in BMSCs and osteoblasts in vitro and in vivo.
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