Kim D, Lee G, Huh Y H, Lee S Y, Park K H, Kim S, Kim J, Koh J, Ryu J
1 Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea.
2 Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea.
J Dent Res. 2017 Jun;96(6):703-711. doi: 10.1177/0022034517690389. Epub 2017 Feb 6.
Recent studies have indicated a potential correlation between rheumatoid arthritis (RA) and periodontal inflammation. We undertook this study to verify whether RA mediates periodontitis-like phenotypes in experimental mouse models of RA and to explore the role of nicotinamide phosphoribosyltransferase (NAMPT) in periodontal inflammation during RA pathogenesis. Periodontal inflammation and alveolar bone loss have been reported in mice with collagen-induced arthritis (CIA) and in genetically modified tumor necrosis factor-α (TNF-α) transgenic (TG) mouse models. Among the adipokines examined in our study, NAMPT expression was markedly upregulated in the periodontal ligament (PDL) tissues in RA mouse models and in human PDL cells stimulated by the proinflammatory cytokines, interleukin (IL) 1β and TNF-α. When NAMPT was overexpressed with the Nampt-synthesizing adenovirus vector (Ad- Nampt), the PDL cells exhibited an increased expression of cytokines (IL6), chemokines (IL8 and chemokine [C-C motif] ligand 5 [CCL5]), inflammatory mediators (cyclooxygenase 2 [COX-2]), and matrix-degrading enzymes (matrix metalloproteinase [MMP] 1 and MMP3). Inhibition of NAMPT by the intracellular NAMPT (iNAMPT) inhibitor, FK866, or by the sirtuin inhibitor, nicotinamide, in PDL cells led to inhibition of the IL1β or Ad- Nampt-induced upregulation of catabolic factors, whereas treatment with recombinant NAMPT protein or blockade of extracellular NAMPT (eNAMPT) with blocking antibody did not. Moreover, NAMPT inhibition by the intraperitoneal or intragingival injection of FK866 in CIA mice inhibited periodontal tissue damage, under conditions of RA. Thus, our results verified the co-occurrence of RA and periodontal inflammation using experimental mouse models of RA, suggesting that iNAMPT in PDL cells plays a pivotal role in the pathogenesis of RA-mediated periodontal inflammation by regulating the expression levels of catabolic genes, such as IL6, IL8, CCL5, COX-2, MMP1, and MMP3.
近期研究表明类风湿关节炎（RA）与牙周炎症之间可能存在关联。我们开展本研究以验证RA是否在RA实验小鼠模型中介导类牙周炎表型，并探究烟酰胺磷酸核糖基转移酶（NAMPT）在RA发病过程中牙周炎症里的作用。在胶原诱导性关节炎（CIA）小鼠以及基因工程改造的肿瘤坏死因子-α（TNF-α）转基因（TG）小鼠模型中，已报道存在牙周炎症和牙槽骨丧失。在我们研究检测的脂肪因子中，NAMPT表达在RA小鼠模型的牙周韧带（PDL）组织以及受促炎细胞因子白细胞介素（IL）-1β和TNF-α刺激的人PDL细胞中显著上调。当用合成Nampt的腺病毒载体（Ad-Nampt）使NAMPT过表达时，PDL细胞表现出细胞因子（IL6）、趋化因子（IL8和趋化因子[C-C基序]配体5[CCL5]）、炎症介质（环氧化酶2[COX-2]）以及基质降解酶（基质金属蛋白酶[MMP]1和MMP3）的表达增加。用细胞内NAMPT（iNAMPT）抑制剂FK866或sirtuin抑制剂烟酰胺抑制PDL细胞中的NAMPT，导致抑制IL1β或Ad-Nampt诱导的分解代谢因子上调，而用重组NAMPT蛋白处理或用阻断抗体阻断细胞外NAMPT（eNAMPT）则无此作用。此外，在CIA小鼠中通过腹腔内或牙龈内注射FK866抑制NAMPT，在RA条件下可抑制牙周组织损伤。因此，我们的结果利用RA实验小鼠模型验证了RA与牙周炎症的共同发生，表明PDL细胞中的iNAMPT通过调节分解代谢基因如IL6、IL8、CCL5、COX-2、MMP1和MMP3的表达水平，在RA介导的牙周炎症发病机制中起关键作用。
