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

• 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
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15370087/
• 关键词: Runx2; Akt; PI3K; osteoblast; chondrocyte; chemotaxis; dexamethazon; statin; Cbfal; デキメサゾン; phosphatidylinositol 3-kinase; 骨芽細胞分化; 軟骨細胞分化; 細胞遊走

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.

我们分析了成骨细胞和软骨细胞的分化和趋化性中Runx2和磷脂酰肌醇3-激酶（PI3K）-AKT信号之间的串扰。 RUNX2和PI3K-AKT信号传导都增强了C3H10T1/2细胞和MC3T3-E1细胞中的成骨细胞分化和趋化性，并增强了软骨分化和ATDC5细胞的进一步成熟。 RUNX2更新了P85，P110β和AKT蛋白，以及PI3K-AKT信号传导增强和显性负（DN）AKT抑制了DNA结合和转录激活的Runx2的能力。因此，runx2和pi3k-akt信号传导串扰并增强成骨细胞和软骨细胞分化。但是，AKT不参与RUNX2的磷酸化。这是通过认为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信号抑制成骨细胞的趋化性。Dexamethazon（DEX）抑制了ATDC5细胞的聚集，这是软骨分化的第一步。 RUNX2和AKT增强了ATDC5细胞的聚集，而DN-RUNX2和DN-AKT抑制了聚集。 DEX抑制了Akt的磷酸化，PI3K亚基蛋白，p85和p110的水平，以及DNA结合和转录激活的Runx2的能力。 DEX通过抑制Akt磷酸化来抑制ATDC5细胞的聚集，然后抑制Runx2和Runx2依赖tepentet转录的DNA结合，从而导致P85和P110蛋白的降低。

项目成果

T.Komori: "Requisite roles of Runx2 and Cbfb in skeletal development"J.Bone Miner.Metab.. 21. 193-197 (2003)

T.Komori：“Runx2 和 Cbfb 在骨骼发育中的必要作用”J.Bone Miner.Metab.. 21. 193-197 (2003)

Expression of dentin matrix protein 1 in tumors causing oncogenic osteomalacia.

牙本质基质蛋白 1 在导致致癌性骨软化的肿瘤中的表达。

• 发表时间: 2004
• 期刊: Modern Pathol. 17
• 作者: S.Toyosawa

Menin Is Required for BMP2-induced osteoblastic differentiation through the interaction with Smad1/5 and Runx2.

Menin 是 BMP2 通过与 Smad1/5 和 Runx2 相互作用诱导的成骨细胞分化所必需的。

• 发表时间: 2004
• 期刊: J Biol.Chem. 279
• 作者: Kawaguchi H;et al.;H.Sowa
• 通讯作者: H.Sowa

Y.Ichikawa: "Evaluation of 9.4-T MR micro-imaging in assessing normal and defective fetal bone development : comparison of MR imaging and histological findings"Bone. (in press).

Y.Ichikawa：“9.4-T MR 显微成像在评估正常和有缺陷的胎儿骨骼发育中的评估：MR 成像和组织学结果的比较”Bone。

A.Kadowaki: "Isolation and characterization of a mesenchymal cell line that differentiates into osteoblasts in response to BMP-2 from calvariae of GFP transgenic mice"Bone. (in press).

A. Kadowaki：“从 GFP 转基因小鼠颅骨中响应 BMP-2 分化为成骨细胞的间充质细胞系的分离和表征”Bone.