Compactin and simvastatin, but not pravastatin, induce bone morphogenetic protein-2 in human osteosarcoma cells.
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-2, a luciferase reporter vector containing the 5'-flanking promoter region of the human BMP-2 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-2 promoter, whereas pravastatin did not. The statin-mediated activation of BMP-2 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.
Sugiyama
M
M
Suntory Biomedical Research Limited, Suntory Institute for Fundamental Research, 1-1-1 Wakayamadai, Osaka, Shimamoto-cho, Mishima-gun, 618-8503, Japan.
Kodama
T
T
Konishi
K
K
Abe
K
K
Asami
S
S
Oikawa
S
S
D000900:Anti-Bacterial Agents / Q000494:pharmacology; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D001859:Bone Neoplasms; D003001:Cloning, Molecular; D004220:Disulfides; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D026121:Indole Alkaloids; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008798:Mevalonic Acid / Q000494:pharmacology; D010024:Osteoporosis / Q000188:drug therapy; D012516:Osteosarcoma; D017035:Pravastatin / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D014162:Transfection; D016212:Transforming Growth Factor beta; D014407:Tumor Cells, Cultured
D000900:Anti-Bacterial Agents; C525718:BMP2 protein, human; C525809:BMP4 protein, human; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D004220:Disulfides; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C001598:chetomin; C012258:mevastatin; D008148:Lovastatin; D019821:Simvastatin; D017035:Pravastatin; D008798:Mevalonic Acid