Akt promotes BMP2-mediated osteoblast differentiation and bone development
Akt promotes BMP2-mediated osteoblast differentiation and bone development
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DOI：
10.1242/jcs.042770
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发表时间：
2009-03-01
影响因子：
4
通讯作者：
Rotwein, Peter
中科院分区：
文献类型：
--
作者：
Mukherjee, Aditi;Rotwein, Peter
IGF-I受体通过局部合成的IGF-I或IGF-II信号传导对正常骨骼发育和骨重塑至关重要。骨形成主要受骨形态发生蛋白（BMPs）调控，BMPs激活由骨特异性转录因子驱动的基因表达程序。在BMP2控制的成骨细胞承诺和分化的间充质干细胞模型中，我们发现pi3激酶抑制剂或显性阴性Akt抑制剂在阻止成骨细胞分化方面与IGF结合蛋白IGFBP5一样有效，而Mek抑制剂则无效。相反，腺病毒编码可诱导活性Akt，能够克服IGFBP5或pi3激酶抑制剂导致的分化阻断，恢复正常的成骨。抑制pi3激酶或Akt并不会阻断bmp2介导的信号传导，因为smad应答基因Sox9和JunB在所有实验条件下都能正常诱导。当在成骨细胞成熟的不同阶段被激活时，显性阴性Akt阻止骨特异性碱性磷酸酶的积累和矿化降低，并通过干扰软骨细胞和成骨细胞的发育和功能，更显著地抑制原代培养中跖骨的纵向生长。我们得出结论，完整的igf诱导的pi3 -激酶- akt信号级联对于bmp2激活的成骨细胞分化和成熟、骨骼发育和生长至关重要，并表明操纵这一途径可以促进骨重塑和骨折修复。
Signaling through the IGF-I receptor by locally synthesized IGF-I or IGF-II is crucial for normal skeletal development and for bone remodeling. Osteogenesis is primarily regulated by bone morphogenetic proteins (BMPs), which activate gene expression programs driven by bone-specific transcription factors. In a mesenchymal stem cell model of osteoblast commitment and differentiation controlled by BMP2, we show that an inhibitor of PI3-kinase or a dominant-negative Akt were as potent in preventing osteoblast differentiation as the IGF binding protein IGFBP5, whereas a Mek inhibitor was ineffective. Conversely, an adenovirus encoding an inducible-active Akt was able to overcome the blockade of differentiation caused by IGFBP5 or the PI3-kinase inhibitor, and could restore normal osteogenesis. Inhibition of PI3-kinase or Akt did not block BMP2-mediated signaling, because the Smad-responsive genes Sox9 and JunB were induced normally under all experimental conditions. When activated during different stages of osteoblast maturation, dominant-negative Akt prevented accumulation of bone-specific alkaline phosphatase and reduced mineralization, and more significantly inhibited the longitudinal growth of metatarsal bones in primary culture by interfering with both chondrocyte and osteoblast development and function. We conclude that an intact IGF-induced PI3-kinase-Akt signaling cascade is essential for BMP2-activated osteoblast differentiation and maturation, bone development and growth, and suggest that manipulation of this pathway could facilitate bone remodeling and fracture repair.