Cell growth regulatory role of Runx2 during proliferative expansion of preosteoblasts.
Cell growth regulatory role of Runx2 during proliferative expansion of preosteoblasts.
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发表时间：
2003-09
期刊：
影响因子：
11.2
通讯作者：
Jitesh Pratap;M. Galindo;S. Zaidi;Diana Vradii;B. Bhat;John A. Robinson;Je-Yong Choi;T. Komori;J. Stein;J. Lian;G. Stein;A. J. Wijnen
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作者：
Jitesh Pratap;M. Galindo;S. Zaidi;Diana Vradii;B. Bhat;John A. Robinson;Je-Yong Choi;T. Komori;J. Stein;J. Lian;G. Stein;A. J. Wijnen
Runx 2（CBFA 1/AML 3/PEBP 2alphaA）转录因子通过激活增殖后成骨细胞中的骨表型基因促进谱系定型和分化。然而，Runx 2在活跃分裂的骨祖细胞中的存在表明该蛋白也可能参与成骨细胞生长的控制。在这里，我们表明，Runx 2是严格调节成骨细胞的细胞周期进入和退出。我们使用来自野生型和Runx 2缺陷小鼠（即，Runx 2（-/-）和Runx 2（DeltaC/DeltaC））。Runx 2（DeltaC/DeltaC）小鼠表达缺乏Runx 2 COOH末端的蛋白质，其整合了几种细胞增殖相关的信号传导途径（例如，Smad、Yes/Src、丝裂原活化蛋白激酶和视网膜母细胞瘤蛋白）。来自Runx 2（-/-）或Runx 2（DeltaC/DeltaC）突变小鼠的颅骨细胞而不是胚胎成纤维细胞表现出增加的细胞生长速率，如DNA合成和G（1）-S期标志物（例如，细胞周期蛋白E）。通过腺病毒递送将Runx 2重新引入Runx 2（-/-）颅骨细胞恢复严格的细胞生长控制。因此，Runx 2调节正常的成骨细胞增殖，而COOH末端区域是这种生物学功能所必需的。我们认为Runx 2通过支持退出细胞周期和激活促进骨细胞表型发育的基因，在关键的发育过渡期促进成骨细胞成熟。
The Runx2 (CBFA1/AML3/PEBP2alphaA) transcription factor promotes lineage commitment and differentiation by activating bone phenotypic genes in postproliferative osteoblasts. However, the presence of Runx2 in actively dividing osteoprogenitor cells suggests that the protein may also participate in control of osteoblast growth. Here, we show that Runx2 is stringently regulated with respect to cell cycle entry and exit in osteoblasts. We addressed directly the contribution of Runx2 to bone cell proliferation using calvarial osteoblasts from wild-type and Runx2-deficient mice (i.e., Runx2(-/-) and Runx2(DeltaC/DeltaC)). Runx2(DeltaC/DeltaC) mice express a protein lacking the Runx2 COOH terminus, which integrates several cell proliferation-related signaling pathways (e.g., Smad, Yes/Src, mitogen-activated protein kinase, and retinoblastoma protein). Calvarial cells but not embryonic fibroblasts from Runx2(-/-) or Runx2(DeltaC/DeltaC) mutant mice exhibit increased cell growth rates as reflected by elevations of DNA synthesis and G(1)-S phase markers (e.g., cyclin E). Reintroduction of Runx2 into Runx2(-/-) calvarial cells by adenoviral delivery restores stringent cell growth control. Thus, Runx2 regulates normal osteoblast proliferation, and the COOH-terminal region is required for this biological function. We propose that Runx2 promotes osteoblast maturation at a key developmental transition by supporting exit from the cell cycle and activating genes that facilitate bone cell phenotype development.