Circadian rhythm disruption is thought to be associated with periodontitis, and molecular clock genes play critical roles in regulating bone homeostasis. However, the specific contribution of molecular clock genes to alveolar bone resorption caused by periodontitis is poorly understood. In this study, we introduced a novel Periodontitis Circadian Rhythm Score (PeriCRS) model that was established through machine learning using periodontal transcriptomic data from periodontitis clinical cohorts in the Gene Expression Omnibus (GEO) database. This approach revealed the potential regulatory role of circadian rhythm disruption in periodontitis and identified key molecular clock genes associated with alveolar bone destruction. Moreover, we established an experimental periodontitis model with circadian rhythm disturbance via periodontal ligation in mice exposed to a 6-h advanced LD12:12 cycle every 2 d. Our bioinformatics analysis revealed that NR1D1, which encodes REV-ERBα, is a pivotal factor in the impact of circadian rhythm disruption on periodontitis in periodontal tissues. Next, we confirmed the abnormal expression of the molecular clock gene Rev-erbα in inflammatory periodontal tissue in mice and confirmed that circadian rhythm disruption altered REV-ERBα expression. Furthermore, the activation of REV-ERBα with the agonist SR9009 notably decreased RANKL-induced osteoclast differentiation and suppressed the expression of osteoclast-related factors. Subsequent in vivo experiments demonstrated that SR9009 mitigated alveolar bone loss caused by periodontitis. Mechanistically, we found that the IL-22-STAT3 pathway inhibited REV-ERBα expression and modulated RANKL-induced osteoclast differentiation in vitro. Our results elucidate the role of REV-ERBα in osteoclastogenesis and suggest a potential new therapeutic avenue for addressing alveolar bone resorption associated with periodontitis.

中文翻译：

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REV-ERBα 抑制破骨细胞生成并防止牙槽骨流失


昼夜节律紊乱被认为与牙周炎有关，分子钟基因在调节骨稳态中起关键作用。然而，分子钟基因对牙周炎引起的牙槽骨吸收的具体贡献知之甚少。在这项研究中，我们引入了一种新的牙周炎昼夜节律评分 （PeriCRS） 模型，该模型是通过机器学习使用来自基因表达综合 （GEO） 数据库中牙周炎临床队列的牙周转录组学数据建立的。这种方法揭示了昼夜节律破坏在牙周炎中的潜在调节作用，并确定了与牙槽骨破坏相关的关键分子时钟基因。此外，我们建立了一个实验性牙周炎模型，该模型通过牙周结扎在每 2 天暴露于 6 小时高级 LD12：12 周期的小鼠中紊乱。我们的生物信息学分析显示，编码 REV-ERBα 的 NR1D1 是昼夜节律破坏对牙周组织牙周炎影响的关键因素。接下来，我们证实了小鼠炎症牙周组织中分子钟基因 Rev-erbα 的异常表达，并证实昼夜节律破坏改变了 REV-ERBα 的表达。此外，激动剂 SR9009 激活 REV-ERBα 显著降低 RANKL 诱导的破骨细胞分化并抑制破骨细胞相关因子的表达。随后的体内实验表明，SR9009 减轻了牙周炎引起的牙槽骨丢失。从机制上讲，我们发现 IL-22-STAT3 通路在体外抑制 REV-ERBα 表达并调节 RANKL 诱导的破骨细胞分化。 我们的结果阐明了 REV-ERBα 在破骨细胞生成中的作用，并为解决与牙周炎相关的牙槽骨吸收提出了一种潜在的新治疗途径。