title: Lactone form 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) stimulate the osteoblastic differentiation of mouse periodontal ligament cells via the ERK pathway.
abstract: OBJECTIVE
  Recent studies reported that the lactone forms of 3-hydroxy- 3-methylglutaryl-coenzyme A reductase inhibitors, which are also known as statins, have a bone stimulatory effect. However, there are few reports on the effect of statins on periodontal ligament cells. This study examined the statin-induced osteoblastic differentiation of mouse periodontal ligament cells as well as its mechanism.
  
  
  METHODS
  Mouse periodontal ligament cells were cultured with lovastatin or simvastatin, and their viability was measured. The levels of alkaline phosphatase (ALP), osteocalcin, bone sialoprotein and bone morphogenetic protein-2 mRNA expression were evaluated by RT-PCR. The osteoblastic differentiation was characterized by the ALP activity and Alizarin Red-S staining for calcium deposition. The activity of the osteocalcin gene (OG2) and synthetic osteoblast-specific elements (6× OSE) promoter with statins was also measured using a luciferase assay. For the signal mechanism of statins, the ERK1/2 MAPK activity was determined by western blot analysis.
  
  
  RESULTS
  A statin treatment at concentrations < 1 μM did not affect the cell viability. Lovastatin or simvastatin at 0.1 μM increased the levels of ALP, osteocalcin, bone sialoprotein and bone morphogenetic protein-2 mRNA in mouse periodontal ligament cells. In addition, the ALP activity, mineralized nodule formation and OG2 and OSE promoter activity were higher in the lovastatin- or simvastatin-treated cells than the control cells. Western blot analysis confirmed that the statins stimulated the phosphorylation of ERK1/2.
  
  
  CONCLUSIONS
  Lovastatin and simvastatin may stimulate the osteoblastic differentiation of periodontal ligament cells via the ERK1/2 pathway. This suggests that the statins may be useful for regenerating periodontal hard tissue.
authors.affiliation: Department of Periodontology, Chonnam National University School of Dentistry and Dental Science Research Institute, Gwangju, South Korea.
authors.forename: I S
authors.initials: IS
authors.lastname: Kim
authors.forename: B C
authors.initials: BC
authors.lastname: Jeong
authors.forename: O S
authors.initials: OS
authors.lastname: Kim
authors.forename: Y J
authors.initials: YJ
authors.lastname: Kim
authors.forename: S E
authors.initials: SE
authors.lastname: Lee
authors.forename: K N
authors.initials: KN
authors.lastname: Lee
authors.forename: J T
authors.initials: JT
authors.lastname: Koh
authors.forename: H J
authors.initials: HJ
authors.lastname: Chung
mesh_terms: D000469:Alkaline Phosphatase / Q000032:analysis; D000818:Animals; D000880:Anthraquinones; D015153:Blotting, Western; D055396:Bone Morphogenetic Protein 2 / Q000032:analysis; D002070:Butadienes / Q000494:pharmacology; D002113:Calcification, Physiologic / Q000187:drug effects; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004396:Coloring Agents; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D058574:Integrin-Binding Sialoprotein / Q000032:analysis; D008148:Lovastatin / Q000494:pharmacology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology; D010006:Osteoblasts / Q000187:drug effects*; D015675:Osteocalcin / Q000032:analysis; D010513:Periodontal Ligament / Q000166:cytology* / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000880:Anthraquinones; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D002070:Butadienes; D004396:Coloring Agents; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D058574:Integrin-Binding Sialoprotein; D009570:Nitriles; C113580:U 0126; D015675:Osteocalcin; C004468:Alizarin Red S; D008148:Lovastatin; D019821:Simvastatin; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D000469:Alkaline Phosphatase