Statin Promotes the INduction of TGF-β1, BMP-2 and the Differentiatiation to Odontoblast in Human Dental Pulp Cells

Abstract

It is accepted that statins widely used as cholesterol-lowering drugs induce bone formation or expression of BMP-2 on several osteogenic cells. Since the statins may induce dentin regeneration on dental treatment, the effects of simvastatin, which is one type of statins, on the induction of odontoblastic differentiation in human dental pulp cells (HDPC) were examined. Alkaline phosphatase (ALP) activity as an index of odontoblastic differentiation in HDPC was measured after the application of simvastatin. and the gene expressions of growth factors (BMP-2 and TGF-β1) were analyzed by the method of luciferase reporter gene assay and RT-PCR. The expressions of specific dentin proteins were also analyzed by RT-PCR. When the HDPC was cultured with adding the simvastatin, the ALP activity of HDPC was decreased according to the simvastatin dose. When both TGF-β1 and BMP-2 were applied together, they decreased multiplicatively the ALP activity similar to the application of simvastatin, although TGF-β1 increased the ALP activity of HDPC whereas BMP-2 reduced the activity. The increases of TGF-β1 and BMP-2 and their mRNAs in HDPC culture with adding simvastatin were detected by luciferase reporter gene assay and RT-PCR, respectively. Since simvastatin inhibits choresterol synthesis via the inhibition of mevalonic acid synthesis, the effect of adding mevalonic acid in HDPC culture with simvastatin was examined. The result showed that it reduced the expression of both TGF-β1 and BMP-2. This indicates that the inhibition of mevalonic acid synthesis by simvastatin enhances the expression of TGF-β1 and BMP-2 of HDPC. In long-term culture of HPDC with adding simvastatin, the expression of dentin sialophosphoprotein (DSPP) was increased by the detection of RT-PCR. The result shows that simvastatin enhances the promotion of odontoblastic differentiation of HPDC. These results indicate that simvastatin enhances the expression of TGF-β1 and BMP-2 and promotes odontoblastic differentiation of HPDC. Simvastatin may thus be useful for dentin regeneration on tooth treatment of dental pulp disease.