title: Simvastatin alleviates the progression of periapical lesions by modulating autophagy and apoptosis in osteoblasts.
abstract: BACKGROUND
  Autophagy is a process for recycling intracellular organelles as a survival mechanism. Apoptosis has important biological roles in the pathogenesis of many diseases. This study elucidated the effect of simvastatin on autophagy/apoptosis in MC3T3E1 murine osteoblastic cells and also the significance of this action on the progression of induced rat apical periodontitis.
  
  
  METHODS
  We examined the H2O2-stimulated expression of LC3-II (an autophagy marker) and poly (adenosine phosphate ribose) polymerase (PARP) fragmentation (an apoptosis marker) in MC3T3E1 by Western analysis. In a rat model of induced apical periodontitis, the relation between disease progression and osteoblastic expression of Beclin-1 (an autophagy marker) and terminal deoxyuridine triphosphate nick end-labeling (an apoptosis marker) was studied by radiographic and immunohistochemistry analyses.
  
  
  RESULTS
  Western blot showed elevated levels of LC3-II and PARP cleavage after H2O2 treatment. An autophagy inhibitor 3-methyladenine promoted whereas rapamycin (an autophagy enhancer) diminished H2O2-induced PARP cleavage. Simvastatin enhanced H2O2-induced LC3-II formation and simultaneously decreased PARP fragmentation. Radiography and immunohistopathology demonstrated that simvastatin reduced the number of apoptotic osteoblasts and the extension of periapical lesions in rats. The number of Beclin-1-synthesizing osteoblasts also increased markedly after simvastatin treatment.
  
  
  CONCLUSIONS
  We found a negative relation between autophagy and apoptosis in osteoblastic cells. In addition, simvastatin suppressed apoptosis and enhanced autophagy both in vitro and in vivo. Our data implied that simvastain might alleviate the progression of apical periodontitis by promoting autophagy to protect osteoblasts from turning apoptotic.
authors.affiliation: School of Dentistry, Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, and Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Eddie Hsiang-Hua
authors.initials: EH
authors.lastname: Lai
authors.forename: Chi-Yuan
authors.initials: CY
authors.lastname: Hong
authors.forename: Sang-Heng
authors.initials: SH
authors.lastname: Kok
authors.forename: Kuo-Liang
authors.initials: KL
authors.lastname: Hou
authors.forename: Ling-Hsiu
authors.initials: LH
authors.lastname: Chao
authors.forename: Li-Deh
authors.initials: LD
authors.lastname: Lin
authors.forename: Mu-Hsiung
authors.initials: MH
authors.lastname: Chen
authors.forename: Ping-Han
authors.initials: PH
authors.lastname: Wu
authors.forename: Sze-Kwan
authors.initials: SK
authors.lastname: Lin
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis; D010006:Osteoblasts / Q000187:drug effects*; D010485:Periapical Periodontitis / Q000188:drug therapy*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000893:Anti-Inflammatory Agents; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D019821:Simvastatin; D006861:Hydrogen Peroxide; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases