Sirtuin 6 Modulates Hypoxia-induced Apoptosis in Osteoblasts via Inhibition of Glycolysis: Implication for Pathogenesis of Periapical Lesions.

Abstract

INTRODUCTION:

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: Sang-Heng Kok, Kuo-Liang Hou, Chi-Yuan Hong, Ling-Hsiu Chao, Eddie Hsiang-Hua Lai, Han-Wei Wang, Hsiang Yang, Chia-Tung Shun, Juo-Song Wang, Sze-Kwan Lin
• Journal: Journal of endodontics (J Endod) Vol. 41 Issue 10 Pg. 1631-7 (Oct 2015) ISSN: 1878-3554 [Electronic] United States
• PMID: 26187426 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Chemical References

• Isoenzymes
• L-Lactate Dehydrogenase
• Lactate Dehydrogenase 5
• Poly(ADP-ribose) Polymerases
• SIRT6 protein, human
• Sirtuins

Topics

• Adult
• Animals
• Apoptosis
• Cells, Cultured
• Glycolysis
• Humans
• Hypoxia (pathology)
• Isoenzymes (metabolism)
• L-Lactate Dehydrogenase (metabolism)
• Lactate Dehydrogenase 5
• Models, Animal
• Osteoblasts (pathology)
• Periapical Periodontitis (metabolism, pathology)
• Poly(ADP-ribose) Polymerases (metabolism)
• Rats, Sprague-Dawley
• Sirtuins (metabolism)
• Young Adult