Ye Lanxiang, Mei Gang, Liu Huan, Zhong Rong, Tang Qingming, Yuan Zhenglin
Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Int Endod J. 2025 May;58(5):744-756. doi: 10.1111/iej.14201. Epub 2025 Jan 27.
Circadian rhythm disruption (CRD) affects the expression levels of a range of biological clock genes, such as brain and muscle ARNT-Like-1 (BMAL1), which is considered to be an important factor in triggering or exacerbating inflammatory response. However, the underlying effect of CRD on the pathogenesis of apical periodontitis, a common oral inflammatory disease, currently remains unknown. Exploring the effects and pathogenic mechanisms of CRD on apical periodontitis will be beneficial in providing new ideas for the prevention and treatment of apical periodontitis.
The cross-sectional study was conducted among patients with apical periodontitis visiting to hospital. Rat models combining CRD and apical periodontitis were constructed, and the destruction of periapical alveolar bone was assessed by Micro-CT, H&E, and TRAP staining assay. Rat periapical alveolar bone tissues were collected for RT-qPCR and immunohistochemistry to further detect the expression of periapical biological clock genes. A model of apical periodontitis was constructed using Bmal1 and WT rats to further verify the key role played by Bmal1. Finally, rats raised in CRD environment were intraperitoneally injected with melatonin to restore the circadian rhythm, and the periapical alveolar bone repair was observed by Masson's staining and staining of osteogenic markers (ALP, RUNX2).
A close association between CRD and acute exacerbation of chronic apical periodontitis (CAP) in patients was first found in an epidemiological survey. By constructing animal models of CRD and apical periodontitis, it was found that CRD could aggravate the inflammatory stress of apical periodontitis and even drive the acute exacerbation of CAP. Further investigations suggested that the expression of crucial clock genes, especially Bmal1, were significantly disrupted in the periapical tissue of apical periodontitis. In addition, the periapical tissue from Bmal1 knockout rat displayed stronger inflammatory response and more severe alveolar bone destruction in apical periodontitis. Restoring circadian rhythm by melatonin supplementation could effectively alleviate both the inflammatory response and alveolar bone loss in apical periodontitis.
CRD is a novel trigger in aggravating the inflammatory response and alveolar bone loss of apical periodontitis. Melatonin is expected to be used in the dental clinic as an important adjunctive therapy strategy for the healing of periapical tissue in apical periodontitis.
昼夜节律紊乱（CRD）会影响一系列生物钟基因的表达水平，如脑和肌肉芳香烃受体核转位蛋白样蛋白1（BMAL1），其被认为是引发或加剧炎症反应的一个重要因素。然而，CRD对常见口腔炎症性疾病根尖周炎发病机制的潜在影响目前仍不清楚。探索CRD对根尖周炎的影响及其致病机制将有助于为根尖周炎的预防和治疗提供新思路。
对到医院就诊的根尖周炎患者进行横断面研究。构建CRD与根尖周炎相结合的大鼠模型，通过显微CT、苏木精-伊红染色（H&E）和抗酒石酸酸性磷酸酶染色（TRAP）检测根尖周牙槽骨的破坏情况。收集大鼠根尖周牙槽骨组织进行逆转录-定量聚合酶链反应（RT-qPCR）和免疫组织化学检测，以进一步检测根尖周生物钟基因的表达。使用Bmal1基因敲除大鼠和野生型大鼠构建根尖周炎模型，以进一步验证Bmal1所起的关键作用。最后，对饲养在CRD环境中的大鼠腹腔注射褪黑素以恢复昼夜节律，通过Masson染色和成骨标志物（碱性磷酸酶、RUNX2）染色观察根尖周牙槽骨的修复情况。
在一项流行病学调查中首次发现患者的CRD与慢性根尖周炎（CAP）急性加重之间存在密切关联。通过构建CRD与根尖周炎的动物模型，发现CRD可加重根尖周炎的炎症应激，甚至促使CAP急性加重。进一步研究表明，关键生物钟基因，尤其是Bmal1，在根尖周炎根尖周组织中的表达明显紊乱。此外，Bmal基因敲除大鼠的根尖周组织在根尖周炎中表现出更强的炎症反应和更严重的牙槽骨破坏。补充褪黑素恢复昼夜节律可有效减轻根尖周炎的炎症反应和牙槽骨丢失。
CRD是加重根尖周炎炎症反应和牙槽骨丢失的一个新诱因。褪黑素有望作为根尖周炎根尖周组织愈合的重要辅助治疗策略应用于牙科临床。
