Study On The Effects Of ATRA And BMP9 On Proliferation And Osteogenic Differentiation Of Human Osteosarcoma Cells And The Possible Mechanisms

Osteosarcoma(OS)is the most common malignant bone tumour and is considered to be a disease caused by a dysfunction in differentiation.Bone morphogenetic protein 9(BMP9)is the most potent osteogenic factor in mesenchymal stem cells,but it cannot induce osteogenic differentiation in OS cells;this might be one of the determinants in the pathogenesis of OS.All-trans-retinoic acid(ATRA)can induce osteogenic differentiation of OS cells and potentiate BMP9-induced osteogenesis in preadipocytes.However,the concomitant effect of ATRA and BMP9 in OS cells is unclear;therefore,in the present study,we focused on this topic.The results showed that BMP9 significantly promoted the proliferation of human OS 143 B cells and did not induce osteogenic differentiation of cells in vitro(p<0.01).ATRA inhibited proliferation and induced osteogenesis in 143 B cells;these effects could be enhanced by BMP9 overexpression(p<0.01).ATRA could significantly increase the level of phosphorylated p38 MAPK(p-p38)in 143 B cells,while BMP9 did not have any significant effect,and ATRA could up-regulate the expression of endogenous BMP9 of 143 B cells.Notably,BMP9 overexpression significantly enhanced the ability of ATRA to increase the levels of p-p38.Both the osteogenic differentiation and the anti-proliferative activity of BMP9 in the presence of ATRA decreased upon treatment with a specific inhibitor of p38 MAPK(SB203580)(p<0.01).This study indicates that the osteogenic differentiation ability of BMP9 in 143 B cells can be restored by ATRA,and the combination of BMP9 and ATRA generated a stronger anti-proliferative effect on 143 B cells than ATRA alone.This result may be due to the activation of the p38 MAPK pathway.