title: Sirtuin 6 Modulates Hypoxia-induced Apoptosis in Osteoblasts via Inhibition of Glycolysis: Implication for Pathogenesis of Periapical Lesions.
abstract: BACKGROUND
  Osteoblast apoptosis is important in the regulation of inflammatory bone resorption. Hypoxia resulting from inflammation enhances glycolysis and apoptosis. Sirtuin 6 (SIRT6) is a modulator of glucose metabolism and apoptosis. In the study we assessed the role of SIRT6 in hypoxia-induced glycolysis and apoptosis in osteoblasts, with special attention on the significance of these cellular processes in periapical lesions.
  
  
  METHODS
  Human bone marrow-derived osteoblasts were cultured under hypoxia. Expression of lactate dehydrogenase A was examined by Western blot, and production of lactate was measured by colorimetric assay. Cleavage of poly (adenosine diphosphate ribose) polymerase was used as an apoptosis marker and assessed by Western blot. SIRT6 was overexpressed in osteoblasts by lentiviral gene transduction, and then glycolytic and apoptotic responses were studied. In a rat model of bacteria-induced periapical lesions, expressions of SIRT6 and markers of glycolysis and apoptosis in osteoblasts were examined.
  
  
  RESULTS
  Hypoxia enhanced lactate dehydrogenase A expression and lactate production in osteoblasts. Poly (adenosine diphosphate ribose) polymerase cleavage was induced by hypoxia or lactate treatment. SIRT6 suppressed hypoxia-augmented glycolysis and inhibited apoptosis induced by hypoxia or lactate treatment. Expression of SIRT6 in osteoblasts was downregulated by hypoxia and inflammatory mediators. Development of periapical lesions in rats was associated with decreased expression of SIRT6 and increased glycolysis and apoptosis in osteoblasts.
  
  
  CONCLUSIONS
  Our study suggested that hypoxia-induced apoptosis of osteoblasts is dependent on glycolytic activity. SIRT6 is a negative regulator of inflammation and may alleviate periapical lesions by suppressing osteoblastic glycolysis and apoptosis.
authors.affiliation: Department of Dentistry, School of Dentistry, College of Medicine, Taipei, Taiwan; Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Sang-Heng
authors.initials: SH
authors.lastname: Kok
authors.affiliation: Graduate Institute of Clinical Dentistry, School of Dentistry, College of Medicine, Taipei, Taiwan.
authors.forename: Kuo-Liang
authors.initials: KL
authors.lastname: Hou
authors.affiliation: Department of Dentistry, School of Dentistry, College of Medicine, Taipei, Taiwan; Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan; College of Bio-Resources and Agriculture, National Taiwan University, Taipei, Taiwan.
authors.forename: Chi-Yuan
authors.initials: CY
authors.lastname: Hong
authors.affiliation: Department of Dentistry, School of Dentistry, College of Medicine, Taipei, Taiwan.
authors.forename: Ling-Hsiu
authors.initials: LH
authors.lastname: Chao
authors.affiliation: Department of Dentistry, School of Dentistry, College of Medicine, Taipei, Taiwan; Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Eddie
authors.initials: E
authors.lastname: Hsiang-Hua Lai
authors.affiliation: Department of Dentistry, School of Dentistry, College of Medicine, Taipei, Taiwan; Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Han-Wei
authors.initials: HW
authors.lastname: Wang
authors.affiliation: Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Hsiang
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Forensic Medicine and Pathology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chia-Tung
authors.initials: CT
authors.lastname: Shun
authors.affiliation: Department of Dentistry, School of Dentistry, College of Medicine, Taipei, Taiwan; Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Juo-Song
authors.initials: JS
authors.lastname: Wang
authors.affiliation: Department of Dentistry, School of Dentistry, College of Medicine, Taipei, Taiwan; Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan. Electronic address: sklin7400@ntu.edu.tw.
authors.forename: Sze-Kwan
authors.initials: SK
authors.lastname: Lin
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D006019:Glycolysis; D006801:Humans; D000860:Hypoxia / Q000473:pathology*; D007527:Isoenzymes / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D000080864:Lactate Dehydrogenase 5; D023421:Models, Animal; D010006:Osteoblasts / Q000473:pathology*; D010485:Periapical Periodontitis / Q000378:metabolism* / Q000473:pathology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D037761:Sirtuins / Q000378:metabolism*; D055815:Young Adult
chemical_list: D007527:Isoenzymes; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D011065:Poly(ADP-ribose) Polymerases; C516592:SIRT6 protein, human; D037761:Sirtuins
keywords: Apical periodontitis; SIRT6; apoptosis; glycolysis; hypoxia; osteoblasts