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

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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.