Circadian rhythm disruption affects cellular senescence through the BMAL1/CRY2/PER1 signaling pathway in periodontitis.

Abstract

Accelerated cellular senescence may be a key process in the progression of periodontitis, as it integrates the devastating effects of the major risk factors for periodontitis. Circadian rhythm disruption (CRD) affects the expression levels of multiple genes, such as brain and muscle ARNT-Like-1 (BMAL1), which is thought to be an important trigger or exacerbator of periodontitis. Even though CRD mechanisms are acknowledged to control cellular senescence, their effect on the senescence that happens during periodontitis is not well defined. This research aimed to explore the role and pathogenic mechanism of CRD in periodontitis and the involvement of cellular senescence, with the purpose of providing innovative ideas for the prevention and treatment of periodontitis. A rat model combining CRD and periodontitis was established. Periodontal lesions were assessed via histological staining. The expression levels of core circadian genes and senescence markers were evaluated. Inflammatory mediators related to the senescence-associated secretory phenotype (SASP) were quantified. The BMAL1 agonist SR8278 was employed to verify the key role of BMAL1 and the BMAL1/cryptochrome 2 (CRY2)/period circadian regulator 1 (PER1) signaling pathway. Finally, the effect of BMAL1 modulation on cellular senescence was examined in lipopolysaccharide (LPS)-induced human periodontal ligament cells (hPDLCs). CRD exacerbated experimental periodontitis lesions and aggravated the periodontal tissue senescence phenotype. BMAL1/CRY2/PER1 gene levels were down-regulated in a model of CRD-complexed periodontitis, and restoration of BMAL1 levels could alleviate CRD-exacerbated periodontitis by attenuating the periodontal tissue senescence phenotype. Interestingly, LPS exposure resulted in increased cellular senescence and decreased BMAL1/CRY2/PER1 in hPDLCs. Knockdown of BMAL1 resulted in further upregulation of cellular senescence in hPDLCs, whereas overexpression of BMAL1 inhibited LPS-induced cellular senescence. This study establishes a significant link between CRD and the aggravation of experimental periodontitis, within which a dysregulated BMAL1/CRY2/PER1 axis and an enhanced senescence phenotype are prominent features. This perspective opens new avenues for periodontitis intervention by focusing on circadian rhythm modulation.