title: Sirtuin 6 attenuates periapical lesion propagation by modulating hypoxia-induced chemokine (C-C motif) ligand 2 production in osteoblasts.
abstract: OBJECTIVE
  To investigate the attenuating effect of sirtuin 6 (SIRT6) on hypoxia-induced production of chemokine (C-C motif) ligand 2 (CCL2) by osteoblasts and the relevance of this action on the pathogenesis of periapical lesions.
  
  
  METHODS
  Sirtuin 6 was overexpressed in MC3T3-E1 murine osteoblasts by lentivirus-mediated gene transfer. The relationship between the antiglycolytic/antioxidative activities of SIRT6 and its effect on hypoxia-induced CCL2 production were examined. Pathogenetic relevance of the actions of SIRT6 was assessed in a rat model of induced apical periodontitis. The data were analysed statistically using Student's t-test or one-way analysis of variance (anova) and then a Tukey's multiple comparison test.
  
  
  RESULTS
  In cultured murine osteoblasts, 24-h hypoxic treatment significantly enhanced the generation of reactive oxygen species (P = 0.003), expression of lactate dehydrogenase A (LDHA) and production of lactate (P = 0.007). A reciprocal effect between hypoxia-induced redox imbalance and hypoxia-enhanced glycolysis was noted which in turn augmented the secretion of CCL2. Through its antiglycolytic and antioxidative effects, SIRT6 blocked the vicious cycle to suppress CCL2 production. In normal periapical tissues of rats, strong expression of SIRT6 and low levels of LDHA and 8-OHdG (a marker of oxidative DNA damage) were found in osteoblasts. In induced apical periodontitis, osteoblastic expression of SIRT6 was significantly suppressed (P = 0.001) which was associated with significantly elevated levels of LDHA (P = 0.003) and 8-OHdG (P = 0.004) and significantly enhanced recruitment of macrophages (P = 0.004).
  
  
  CONCLUSIONS
  Sirtuin 6 has a therapeutic effect on periapical lesions through suppression of CCL2 synthesis. The anti-inflammatory action of SIRT6 is closely related to its regulatory activities in cellular metabolism and redox homoeostasis.
authors.affiliation: Graduate Institute of Clinical Dentistry and School of Dentistry, National Taiwan University and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Y-L
authors.initials: YL
authors.lastname: Lee
authors.affiliation: Graduate Institute of Clinical Dentistry and School of Dentistry, National Taiwan University and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: S-K
authors.initials: SK
authors.lastname: Lin
authors.affiliation: Graduate Institute of Clinical Dentistry and School of Dentistry, National Taiwan University and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: K-L
authors.initials: KL
authors.lastname: Hou
authors.affiliation: Graduate Institute of Clinical Dentistry and School of Dentistry, National Taiwan University and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: S-H
authors.initials: SH
authors.lastname: Kok
authors.affiliation: Graduate Institute of Clinical Dentistry and School of Dentistry, National Taiwan University and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: E H-H
authors.initials: EH
authors.lastname: Lai
authors.affiliation: Graduate Institute of Clinical Dentistry and School of Dentistry, National Taiwan University and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: H-W
authors.initials: HW
authors.lastname: Wang
authors.affiliation: Graduate Institute of Clinical Dentistry and School of Dentistry, National Taiwan University and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: J Z-C
authors.initials: JZ
authors.lastname: Chang
authors.affiliation: Graduate Institute of Clinical Dentistry and School of Dentistry, National Taiwan University and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: H
authors.initials: H
authors.lastname: Yang
authors.affiliation: Graduate Institute of Clinical Dentistry and School of Dentistry, National Taiwan University and National Taiwan University Hospital, Taipei, Taiwan.|Department of Prosthodontics, School of Dentistry, China Medical University, Taichong, Taiwan.|College of BioResources and Agriculture, National Taiwan University, Taipei, Taiwan.
authors.forename: C-Y
authors.initials: CY
authors.lastname: Hong
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism*; D010485:Periapical Periodontitis / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D037761:Sirtuins / Q000378:metabolism*
chemical_list: D018932:Chemokine CCL2; D017382:Reactive Oxygen Species; D019344:Lactic Acid; C501860:Sirt6 protein, mouse; D037761:Sirtuins
keywords: apical periodontitis; chemokine (C-C motif) ligand 2; glycolysis; hypoxia; reactive oxygen species; sirtuin 6