Phosphatidylinositol 3 Kinase/Akt Signal Relay Cooperates with Smad in Bone Morphogenetic Protein-2-Induced Colony Stimulating Factor-1 (CSF-1) Expression and Osteoclast Differentiation
Phosphatidylinositol 3 Kinase/Akt Signal Relay Cooperates with Smad in Bone Morphogenetic Protein-2-Induced Colony Stimulating Factor-1 (CSF-1) Expression and Osteoclast Differentiation
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DOI：
10.1210/en.2009-0026
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发表时间：
2009-11-01
期刊：
影响因子：
4.8
通讯作者：
Ghosh-Choudhury, Nandini
中科院分区：
文献类型：
--
作者：
Mandal, Chandi C.;Choudhury, Goutam Ghosh;Ghosh-Choudhury, Nandini
当与成骨细胞共培养时，小鼠脾细胞产生成熟的破骨细胞。集落刺激因子（CSF）-1是单核细胞-巨噬细胞前体细胞分化为破骨细胞前体所需的生长因子。成骨细胞中的骨形态发生蛋白（BMP）信号调节小鼠的骨量，提示BMP在破骨细胞生成中的作用与成骨细胞活性沿着。本报告描述了作为BMP诱导的破骨细胞生成机制的细胞内信号转导串扰调节成骨细胞产生CSF-1。我们最近描述了Smad 1/5参与BMP-2诱导的CSF-1表达和破骨细胞形成。在这项研究中，使用药理学抑制剂和腺病毒（Ad）载体表达显性阴性（DN）磷脂酰肌醇3激酶（PI 3 K），PI 3 K信号传导抑制剂，10号染色体缺失的磷酸酶和张力蛋白同源物（PTEN）或DN Akt激酶，在体外共培养试验中，我们显示了脂激酶级联在BMP-2介导的多核破骨细胞形成和CSF-1 mRNA表达、转录和分泌中的重要作用。抑制PI 3 K/Akt信号传导阻断了Smads 1/5与CSF-1启动子中存在的CSF-1 BMP反应元件的结合，导致Smad依赖性CSF-1转录的减弱。此外，PI 3 K抑制和DN Akt阻止了转录共激活因子CREB（cAMP反应元件结合蛋白）结合蛋白（CBP）与Smads 1/5的结合。总之，这些数据首次证明PI 3 K依赖性Akt活化调节BMP-2诱导的CSF-1表达，并提供成骨细胞辅助破骨细胞分化的机制。（内分泌学150：4989-4998，2009）
Murine spleen cells produce mature osteoclasts when cocultured with osteoblastic cells. Colony-stimulating factor (CSF)-1 is the growth factor required for differentiating the monocyte-macrophage precursor cells into preosteoclasts. Bone morphogenic protein (BMP) signaling in osteoblasts regulates bone mass in mice, suggesting a role of BMP in osteoclastogenesis along with osteoblast activity. The intracellular signal transduction cross talk regulating the osteoblastic production of CSF-1 as a mechanism of BMP-induced osteoclastogenesis is described in this report. We have recently described the involvement of Smad 1/5 in BMP-2-induced CSF-1 expression and osteoclast formation. In this study, using the pharmacological inhibitors and the adenovirus (Ad) vectors expressing dominant-negative (DN) phosphatidylinositol 3 kinase (PI3K), the PI3K-signaling inhibitor, phosphatase and tensin homolog deleted in chromosome 10 (PTEN) or DN Akt kinase in the in vitro coculture assay, we show an essential role of the lipid kinase cascade in BMP-2-mediated multinucleated osteoclast formation and CSF-1 mRNA expression, transcription, and secretion. Inhibition of PI3K/Akt signaling blocked the binding of Smads 1/5 to the CSF-1 BMP-responsive element present in the CSF-1 promoter, resulting in attenuation of Smad-dependent CSF-1 transcription. Furthermore, PI3K inhibition and DN Akt prevented association of the transcriptional coactivator, CREB (cAMP response element binding protein) binding protein (CBP), with Smads 1/5. Together, these data for the first time demonstrate that PI3K-dependent Akt activation regulates BMP-2-induced CSF-1 expression and provides a mechanism for osteoblastic cell-assisted osteoclast differentiation. (Endocrinology 150: 4989-4998, 2009)