Compactin and simvastatin, but not pravastatin, induce bone morphogenetic protein-2 in human osteosarcoma cells
Compactin and simvastatin, but not pravastatin, induce bone morphogenetic protein-2 in human osteosarcoma cells
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DOI：
10.1006/bbrc.2000.2697
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发表时间：
2000-05-19
影响因子：
3.1
通讯作者：
Oikawa, S
中科院分区：
文献类型：
--
作者：
Sugiyama, M;Kodama, T;Oikawa, S
骨形态发生蛋白（BMP）-2是BMP家族的成员，在成骨细胞分化和骨形成中起重要作用。为了发现诱导BMP-S的小分子，构建了含有人BMP-S基因5 '侧翼启动子区的荧光素酶报告载体，并转染人骨肉瘤（HOS）细胞。通过对稳定转染的HOS细胞的内部天然产物库的筛选，分离到真菌代谢物compactin，其被称为3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂。在HOS细胞中，compactin对BMP-2基因启动子活性的刺激似乎是特异性的，因为它对BMP-4或SV 40启动子活性的影响很小，并且在中国仓鼠卵巢（CHO）细胞中没有观察到这种刺激。RT-PCR分析和碱性磷酸酶测定显示，compactin诱导BMP-2 mRNA和蛋白表达增加。与康帕汀一样，辛伐他汀也能激活BMP-S启动子，而普伐他汀则不能。他汀类药物介导的BMP-S启动子的激活被HMG-CoA还原酶的下游代谢产物甲羟戊酸完全抑制，表明该激活是该酶抑制的结果。这些结果表明，他汀类药物，如果他们是有选择性地针对骨，在治疗骨质疏松症或骨折的有益效果。(C)北京大学出版社.
Bone morphogenetic protein (BMP)-2, a member of the BMP family, plays an important role in osteoblast differentiation and bone formation. To discover small molecules that induce BMP-S, a luciferase reporter vector containing the 5'-flanking promoter region of the human BMP-S gene was constructed and transfected into human osteosarcoma (HOS) cells. By the screening of an in-house natural product library with stably transfected HOS cells, a fungal metabolite, compactin, known as an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, was isolated. The stimulation of the promoter activity by compactin seemed to be specific for BMP-2 gene in HOS cells, since it had little effect on BMP-4 or SV40 promoter activity and the stimulation was not observed in Chinese hamster ovary (CHO) cells. RT-PCR analysis and alkaline phosphatase assay revealed that compactin induced an increase in the expression of BMP-2 mRNA and protein. Like compactin, simvastatin also activated the BMP-S promoter, whereas pravastatin did not. The statin-mediated activation of BMP-S promoter was completely inhibited by the downstream metabolite of HMG-CoA reductase, mevalonate, indicating that the activation was a result of the inhibition of the enzyme. These results suggest that statins, if they are selectively targeted to bone, have beneficial effects in the treatment of osteoporosis or bone fracture. (C) 2000 Academic Press.