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Elucidation of the interaction between Akt and Runx2 in the regulation of cell size, chemotaxis, and differentiation of skeletal component cells

阐明 Akt 和 Runx2 在细胞大小、趋化性和骨骼成分细胞分化调节中的相互作用

基本信息

批准号：
15370087
负责人：
KOMORI Toshihisa
金额：
$ 9.86万
依托单位：
Nagasaki University (2004)Osaka University (2003)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

We analyzed the crosstalk between Runx2 and phosphatidylinositol 3-kinase (PI3K)-Akt signaling in the differentiation and chemotaxis of osteoblasts and chondrocytes. Both Runx2 and PI3K-Akt signaling enhanced osteoblast differentiation and chemotaxis in C3H10T1/2 cells and MC3T3-E1 cells, and enhanced chondrogenic differentiation and further maturation in ATDC5 cells. Runx2 upregulated p85, p110β, and Akt proteins, and PI3K-Akt signaling enhanced and dominant negative(dn)Akt suppressed the capacities of Runx2 for DNA binding and transcriptional activation. Therefore, Runx2 and PI3K-Akt signaling crosstalk and enhance osteoblast and chondrocyte differentiation. However, Akt was not involved in the phosphorylation of Runx2. Thus, it is considered that Akt modulates Runx2 function by the phosphorylation of the proteins that form a complex with Runx2. Statin suppressed chemotaxis of osteoblasts by inhibiting Rac-Akt signaling.Dexamethazon(DEX) inhibited the aggregation of ATDC5 cells, which is the first step for the chondrogenic differentiation. Runx2 and Akt enhanced aggregation of ATDC5 cells, while dn-Runx2 and dn-Akt inhibited the aggregation. DEX suppressed phosphrylation of Akt, the level of PI3K subunit proteins, p85 and p110,and the capacity of Runx2 for the DNA binding and transcriptional activation. Thus, DEX inhibits the aggregation of ATDC5 cells by suppressing Akt phosphoorylation, which is followed by the inhibition of DNA binding of Runx2 and Runx2-dependet transcription leading to the decrease in p85 and p110 proteins.

我们分析了 Runx2 和磷脂酰肌醇 3-激酶 (PI3K)-Akt 信号在成骨细胞和软骨细胞的分化和趋化性中的串扰。 Runx2 和 PI3K-Akt 信号传导增强了 C3H10T1/2 细胞和 MC3T3-E1 细胞中的成骨细胞分化和趋化性，并增强了 ATDC5 细胞中的软骨形成分化和进一步成熟。 Runx2 上调 p85、p110β 和 Akt 蛋白，PI3K-Akt 信号传导增强，显性失活 (dn)Akt 抑制 Runx2 的 DNA 结合和转录激活能力。因此，Runx2 和 PI3K-Akt 信号传导串扰并增强成骨细胞和软骨细胞的分化。然而，Akt 不参与 Runx2 的磷酸化。因此，认为 Akt 通过与 Runx2 形成复合物的蛋白质的磷酸化来调节 Runx2 功能。他汀类药物通过抑制Rac-Akt信号传导来抑制成骨细胞的趋化性。地塞米松(DEX)抑制ATDC5细胞的聚集，这是软骨形成分化的第一步。 Runx2和Akt增强ATDC5细胞的聚集，而dn-Runx2和dn-Akt抑制聚集。 DEX 抑制 Akt 磷酸化、PI3K 亚基蛋白、p85 和 p110 的水平以及 Runx2 的 DNA 结合和转录激活能力。因此，DEX 通过抑制 Akt 磷酸化来抑制 ATDC5 细胞的聚集，随后抑制 Runx2 的 DNA 结合和 Runx2 依赖性转录，导致 p85 和 p110 蛋白减少。