RRC ID 61790
著者 Izumo N, Fujita T, Nakamuta H, Koida M.
タイトル Lipophilic statins can be osteogenic by promoting osteoblastic calcification in a Cbfa1- and BMP-2-independent manner.
ジャーナル Methods Find Exp Clin Pharmacol
Abstract 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.
巻・号 23(7)
ページ 389-94
公開日 2001-9-1
DOI 10.1358/mf.2001.23.7.662123
PII 662123
PMID 11771853
MeSH Animals Bone Morphogenetic Protein 2 Bone Morphogenetic Proteins / metabolism* Calcification, Physiologic / drug effects* Calcium / metabolism Cell Line Core Binding Factor Alpha 1 Subunit Core Binding Factors Fatty Acids, Monounsaturated / pharmacology Fluvastatin GTPase-Activating Proteins / antagonists & inhibitors GTPase-Activating Proteins / metabolism Humans Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology* Immunohistochemistry Indoles / pharmacology Lovastatin / analogs & derivatives* Lovastatin / pharmacology Mevalonic Acid / metabolism Mice Neoplasm Proteins* Osteoblasts / cytology Osteoblasts / drug effects* Osteoblasts / metabolism Osteogenesis / drug effects* Phosphates / pharmacology Polyisoprenyl Phosphates / metabolism Pravastatin / pharmacology Protein Prenylation Sesquiterpenes Signal Transduction Transcription Factors / metabolism* Transforming Growth Factor beta / metabolism Tumor Cells, Cultured
リソース情報
ヒト・動物細胞 MC3T3-E1(RCB1126)