Periodontitis-Associated Clock Signaling Impairs Primary Cilia to Promote Periodontal Stem Cell Senescence

To explore circadian involvement in periodontitis and provide insight into mechanisms.

Clinical samples from patients with periodontitis and a ligature-induced periodontitis mouse model were used in the present research. The rhythmic pattern of cortisol, the core circadian rhythm proteins BMAL1 and CLOCK, the expression of senescence markers (p16, p21, and p53), and the percentage and length of primary cilia were detected in hPDLSCs (human periodontal ligament stem cells) exposed to cortisol as an in vitro model of cortisol-associated circadian disruption. BMAL1 expression was manipulated by siRNA transfection to knock down BMAL1 expression, and SR8278 treatment was used to modulate BMAL1-related circadian regulation. Moreover, the effects of SR8278 on the progression of periodontitis were evaluated by micro-CT, mouse behavior tests, the number of primary cilia, and senescence assays.

Patients with periodontitis and ligature-induced periodontitis mice exhibited elevated cortisol levels, reduced BMAL1 expression, increased senescence-associated markers, and decreased primary cilia abundance. Elevated cortisol was associated with circadian disruption, accompanied by reduced BMAL1 expression and impaired ciliary homeostasis. BMAL1 regulated ARL13B expression, a key regulator of ciliogenesis. BMAL1 knockdown impaired Hedgehog signaling and induced hPDLSC senescence. SR8278 partially recovered BMAL1-related circadian alterations and primary cilia abundance while attenuating cellular senescence in both periodontitis model mice and cortisol-treated hPDLSCs.

Collectively, these findings support the involvement of the cortisol-BMAL1-ARL13B pathway in periodontitis-associated primary cilium dysfunction and hPDLSC senescence. Modulation of BMAL1 partially restored primary cilium homeostasis and attenuated periodontal tissue damage, supporting its potential as a therapeutic target for periodontitis.