Periodontitis is a chronic inflammatory disease characterized by progressive alveolar bone destruction and represents a major cause of tooth loss. It has also been associated with systemic inflammatory conditions such as diabetes. Circadian rhythms, governed by clock genes, are essential for maintaining physiological homeostasis across various tissues. Circadian rhythm disruption, such as that caused by night shift work, has been associated with severe periodontitis; however, the underlying mechanisms remain incompletely understood. Period 2 (Per2), a core peripheral clock gene expressed in periodontal tissues, was investigated for its role in inflammatory bone loss under circadian disruption. In a murine ligature model, circadian disruption exacerbated alveolar bone loss, while Per2 deficiency amplified inflammatory responses. Consistently, PER2 knockdown in TNF-α-stimulated human periodontal ligament cells (hPDLCs) led to increased expression of pro-inflammatory cytokines IL-1β and IL-6. Interestingly, Per2 knockout also led to increased basal bone mass compared with wild-type mice. Mechanistically, we found miR-21, a PER2-regulated microRNA, displayed rhythmic expression in hPDLCs and was downregulated following PER2 knockdown. Further investigation demonstrated that the PER2/miR-21 axis negatively regulates osteogenic differentiation under non-inflammatory conditions via TGF-β/SMAD signaling, while under inflammatory conditions, its downregulation failed to suppress PDCD4/NF-κB signaling, resulting in elevated pro-inflammatory cytokine secretion. Finally, local delivery of miR-21 agomir significantly promoted bone recovery after ligature removal. Together, these findings identify PER2 as a key circadian regulator of inflammation-associated bone homeostasis and highlight miR-21 as a potential therapeutic target for bone regeneration in periodontitis.
