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Simvastatin Promotes Osteoblast Differentiation and Mineralization in MC3T3-E1 Cells

https://doi.org/10.1006/bbrc.2000.4232Get rights and content

Abstract

The cholesterol-lowering drug, simvastatin, is a pro-drug of a potent 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor and inhibits cholesterol synthesis in humans and animals. In addition, the bone effects of statins including simvastatin are being studied. We assessed the effects of simvastatin on osteoblastic differentiation in nontransformed osteoblastic cells (MC3T3-E1) and rat bone marrow cells. Simvastatin enhanced alkaline phosphatase (ALP) activity and mineralization in a dose- and time-dependent fashion. This stimulatory effect of the statin was observed at relatively low doses (significant at 10−8 M and maximal at 10−7 M). Northern blot analysis showed that the statin (10−7 M) increased in bone morphogenetic protein-2 as well as ALP mRNA concentrations in MC3T3-E1 cells. Simvastatin (10−7 M) slightly increased in type I collagen mRNA abundance throughout the culture period, whereas it markedly inhibited the gene expression of collagenase-1 between days 14 and 22 of culture. These results indicate that simvastatin has anabolic effects on bone through the promotion of osteoblastic differentiation, suggesting that it could be used for the treatment of common metabolic bone diseases such as osteoporosis.

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    Mundy et al. reported that SIM could enhance bone formation [22,31]. SIM was also shown to promote the osteogenic differentiation and mineralization of MC3T3-E1 cells, upregulate the expression of BMP-2 in osteoblasts and enhance the osteogenic capacity in bone defect sites [29,32,33]. Moreover, SIM can promote angiogenesis through upregulating the secretion of VEGF and the basic fibroblast growth factor (bFGF) [10,34].

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To whom correspondence should be addressed at Department of Biochemistry, Ohu University School of Dentistry, Koriyama 963-8611, Japan. Fax: (81)-24-938-9192. E-mail: [email protected].

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