title: Mechanism of simvastatin on induction of heat shock protein in osteoblasts.
abstract: It has recently been reported that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) stimulate bone formation. However, the mechanism of stimulation of bone metabolism by statins is not precisely clarified. In this study, we investigated whether simvastatin induces heat shock protein (HSP) 27, HSP70, and HSP90 in osteoblast-like MC3T3-E1 cells. Simvastatin increased the levels of HSP27 while having little effect on the levels of HSP70 or HSP90. The effect of simvastatin on HSP27 accumulation was dose dependent. Cycloheximide reduced the accumulation. Simvastatin induced an increase in the levels of mRNA for HSP27. Actinomycin D suppressed the mRNA levels. Simvastatin induced the phosphorylation of p38 mitogen-activated protein (MAP) kinase among the MAP kinase superfamily. SB203580 and PD169316, inhibitors of p38 MAP kinase, suppressed the HSP27 accumulation by simvastatin while SB202474, a negative control of p38 MAP kinase inhibitor, had no effect. SB203580 reduced the simvastatin-increased mRNA levels for HSP27. Lovastatin, another statin, also induced the HSP27 accumulation and SB203580 suppressed the HSP27 accumulation. These results strongly suggest that statins such as simvastatin do not stimulate the induction of HSP70 and HSP90, but do stimulate the induction of HSP27 in osteoblasts and that p38 MAP kinase plays a role in this induction.
authors.affiliation: Department of Pharmacology, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu-shi, Gifu-ken 500-8705, Japan.
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Wang
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Tokuda
authors.forename: Daijiro
authors.initials: D
authors.lastname: Hatakeyama
authors.forename: Kouseki
authors.initials: K
authors.lastname: Hirade
authors.forename: Masayuki
authors.initials: M
authors.lastname: Niwa
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ito
authors.forename: Kanefusa
authors.initials: K
authors.lastname: Kato
authors.forename: Osamu
authors.initials: O
authors.lastname: Kozawa
mesh_terms: D016475:3T3 Cells / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D003513:Cycloheximide / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D007093:Imidazoles / Q000494:pharmacology; D008148:Lovastatin / Q000494:pharmacology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D019821:Simvastatin / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004791:Enzyme Inhibitors; D006360:Heat-Shock Proteins; D007093:Imidazoles; D011725:Pyridines; D012333:RNA, Messenger; D003513:Cycloheximide; D008148:Lovastatin; D019821:Simvastatin; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C408604:2-(4-nitrophenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazole; C093642:SB 203580