Sirtuin 6 attenuates periapical lesion propagation by modulating hypoxia‐induced chemokine (C‐C motif) ligand 2 production in osteoblasts

Abstract

Lee Y-L, Lin S-K, Hou K-L, Kok S-H, Lai EH-H, Wang H-W, Chang JZ-C, Yang H, Hong C-Y. Sirtuin 6 attenuates periapical lesion propagation by modulating hypoxia-induced chemokine (C-C motif) ligand 2 production in osteoblasts. International Endodontic Journal, 51, e74-e86, 2018.Aim 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. Methodology 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 hypoxiaenhanced 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.

Class IIa Histone Deacetylases Drive Toll-like Receptor-Inducible Glycolysis and Macrophage Inflammatory Responses via Pyruvate Kinase M2

“…Given that Hdac7 interacted with Pkm2, we postulated that the proinflammatory functions of Hdac7 might be linked to immuno-metabolic control. Indeed, Mac-Hdac7 macrophages displayed increased LPS-inducible lactate, elevated production of the glycolysis-linked proinflammatory mediators Il-1b (Palsson-McDermott et al, 2015) and Ccl2 (Lee et al, 2018) and reduced Il-10 production (Mills et al, 2016;Figures 3A-3D). These effects were mirrored at the mRNA level (Figures S2A-S2C).…”

Simvastatin alleviates bone resorption in apical periodontitis possibly by inhibition of mitophagy‐related osteoblast apoptosis

“…Regarding the pathogenesis of apical periodontitis, previous experiments have shown a significant elevation of oxidative lesions in osteoblasts of periapical lesions (Lee et al . ). The results of the present study further suggest that hypoxia‐induced oxidative stress in osteoblasts may cause disproportionate mitophagy which is detrimental to cell survival and related to inflammatory bone loss in apical periodontitis.…”

Value of Serum Sirtuin-1 (SIRT1) Levels and SIRT1 Gene Variants in Periodontitis Patients

“…It may also positively alleviate periapical lesions by suppressing osteoblastic glycolysis and apoptosis [ 31 ]. Researchers Lee et al also investigated the ability of SIRT6 to suppress the synthesis of CCL2 (chemokine ligand 2), which may lead to a therapeutic effect on periapical lesions [ 13 ]. As noted by Huang et al, SIRT6 also played a negative role in the differentiation and mineralization of cementoblasts, which was important because of the similar composition of cementum and its importance in homeostasis during periodontal treatment [ 32 ].…”

“…In periodontal diseases, although not directly, some sirtuins ( SIRT4 - and SIRT3 -families) are studied, and there tend to be associations with various pathologies, such as diabetes melitus [ 12 ]. Some members of the SIRT family, especially SIRT6 , tend to have a therapeutic effect on periapical lesions and their treatment by suppressing CCL2 synthesis, which is also associated with regulatory activities in cellular metabolism [ 13 ].…”