Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea.
Hard-tissue Biointerface Research Center, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea.
J Dent Res. 2020 Oct;99(11):1287-1295. doi: 10.1177/0022034520933533. Epub 2020 Jun 12.
The cause of chronic inflammatory periodontitis, which leads to the destruction of periodontal ligament and alveolar bone, is multifactorial. An increasing number of studies have shown the clinical significance of NLRP3-mediated low-grade inflammation in degenerative disorders, but its causal linkage to age-related periodontitis has not yet been elucidated. In this study, we investigated the involvement of the NLRP3 inflammasome and the therapeutic potential of NLRP3 inhibition in age-related alveolar bone loss by using in vivo and in vitro models. The poor quality of alveolar bones in aged mice was correlated with caspase-1 activation by macrophages and elevated levels of IL-1β, which are mainly regulated by the NLRP3 inflammasome, in periodontal ligament and serum, respectively. Aged mice lacking showed better bone mass than age-matched wild-type mice via a way that affects bone resorption rather than bone formation. In line with this finding, treatment with MCC950, a potent inhibitor of the NLRP3 inflammasome, significantly suppressed alveolar bone loss with reduced caspase-1 activation in aged mice but not in young mice. In addition, our in vitro studies showed that the addition of IL-1β encourages RANKL-induced osteoclastogenesis from bone marrow-derived macrophages and that treatment with MCC950 significantly suppresses osteoclastic differentiation directly, irrelevant to the inhibition of IL-1β production. Our results suggest that the NLRP3 inflammasome is a critical mediator in age-related alveolar bone loss and that targeting the NLRP3 inflammasome could be a novel option for controlling periodontal degenerative changes with age.
慢性炎症性牙周炎的病因是多因素的，它会导致牙周韧带和牙槽骨的破坏。越来越多的研究表明，NLRP3 介导的低度炎症在退行性疾病中具有临床意义，但它与年龄相关性牙周炎的因果关系尚未阐明。在这项研究中，我们通过体内和体外模型研究了 NLRP3 炎性体的参与以及 NLRP3 抑制在年龄相关性牙槽骨丢失中的治疗潜力。年老小鼠的牙槽骨质量较差，与巨噬细胞中 caspase-1 的激活以及牙周韧带和血清中 IL-1β水平升高有关，这些主要受 NLRP3 炎性体调节。缺乏 NLRP3 的老年小鼠通过影响骨吸收而不是骨形成的方式，其骨量比同龄野生型小鼠更好。与此一致的是，NLRP3 炎性体的强效抑制剂 MCC950 的治疗显著抑制了老年小鼠的牙槽骨丢失，同时降低了 caspase-1 的激活，但对年轻小鼠没有影响。此外，我们的体外研究表明，IL-1β 的添加促进了骨髓来源的巨噬细胞中 RANKL 诱导的破骨细胞生成，而 MCC950 的治疗直接显著抑制破骨细胞分化，与抑制 IL-1β 的产生无关。我们的研究结果表明，NLRP3 炎性体是年龄相关性牙槽骨丢失的关键介质，靶向 NLRP3 炎性体可能是控制牙周退行性变化的一种新选择。
