Lipophilic statins can be osteogenic by promoting osteoblastic calcification in a Cbfa1- and BMP-2-independent manner.
Mevastatin (3-10 microM) and fluvastatin (0.1-10 microM), but not pravastatin, were found to promote calcification of MC3T3-E1 cells and their subclone MC4, in either the presence or absence of 3 mM inorganic phosphate stimulus. The mechanism of action was examined. Gel retardation assay and immunocytochemical analysis of core binding factor (Cbfa1) revealed that mevastatin and fluvastatin completed the nuclear export of Cbfa1, possibly thereby reducing the induction of the stably transfected p6OSE2-luc gene, and then promoted Cbfa1-independent calcification, which invariably occurred in both wild type and dominant negative Cbfa1-expressing cells. The induction of the bone morphogenetic protein-2 (BMP-2) gene promoter failed to respond to the statins. All the effects of the cell-permeable statins were negated by mevalonate pathway metabolites (geranylgeranylpyrophosphate > farnesylpyrophosphate > mevalonate) and reproduced by toxin B (a Rho-specific inhibitor), but not totally by Y27632 (a ROCK-specific inhibitor). The results suggest that lipophilic statins can be osteogenic by promoting Cbfa1- and BMP-2-independent calcification processes.
Izumo
N
N
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan.
Fujita
T
T
Nakamuta
H
H
Koida
M
M
D000818:Animals; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002113:Calcification, Physiologic / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D050659:Core Binding Factor Alpha 1 Subunit; D050660:Core Binding Factors; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D000077340:Fluvastatin; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D009363:Neoplasm Proteins; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D010710:Phosphates / Q000494:pharmacology; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D017035:Pravastatin / Q000494:pharmacology; D017368:Protein Prenylation; D012717:Sesquiterpenes; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014407:Tumor Cells, Cultured
C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D050660:Core Binding Factors; D005229:Fatty Acids, Monounsaturated; D020690:GTPase-Activating Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D009363:Neoplasm Proteins; D010710:Phosphates; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C085379:rho GTPase-activating protein; C012258:mevastatin; D000077340:Fluvastatin; C004808:farnesyl pyrophosphate; D008148:Lovastatin; D017035:Pravastatin; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid; D002118:Calcium