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.
Int Endod J. 2018 Feb;51 Suppl 2:e74-e86. doi: 10.1111/iej.12742. Epub 2017 Feb 27.
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.
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.
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).
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.
研究组蛋白去乙酰化酶 6（SIRT6）对成骨细胞缺氧诱导趋化因子（C-C 基序）配体 2（CCL2）产生的抑制作用及其与根尖周病发病机制的相关性。
通过慢病毒介导的基因转移在 MC3T3-E1 鼠成骨细胞中过表达 SIRT6。检测 SIRT6 的抗糖酵解/抗氧化活性与其抑制缺氧诱导的 CCL2 产生之间的关系。在诱导的根尖周炎大鼠模型中评估 SIRT6 作用的发病相关性。使用学生 t 检验或单因素方差分析（anova）然后 Tukey 多重比较检验对数据进行统计学分析。
在培养的鼠成骨细胞中，24 小时缺氧处理显著增强了活性氧（ROS）的产生（P=0.003）、乳酸脱氢酶 A（LDHA）的表达和乳酸的产生（P=0.007）。缺氧诱导的氧化还原失衡与缺氧增强糖酵解之间存在相互作用，从而增强了 CCL2 的分泌。SIRT6 通过其抗糖酵解和抗氧化作用阻断了抑制 CCL2 产生的恶性循环。在大鼠正常根尖周组织中，成骨细胞中 SIRT6 的表达较强，LDHA 和 8-羟基脱氧鸟苷（氧化 DNA 损伤的标志物）的水平较低。在诱导的根尖周炎中，成骨细胞中 SIRT6 的表达明显受到抑制（P=0.001），同时 LDHA（P=0.003）和 8-羟基脱氧鸟苷（P=0.004）的水平显著升高，巨噬细胞的募集明显增强（P=0.004）。
SIRT6 通过抑制 CCL2 合成对根尖周病变具有治疗作用。SIRT6 的抗炎作用与其在细胞代谢和氧化还原平衡中的调节活性密切相关。
