Circadian disruption accelerates the progression of experimental periodontitis via PER2/miR-21-mediated inflammatory and osteogenic dysregulation

May 22, 2026Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

Disrupted body clocks speed up gum disease by affecting inflammation and bone changes through PER2 and miR-21

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Abstract

Circadian disruption exacerbates alveolar bone loss in periodontitis, with PER2 deficiency amplifying inflammatory responses.

Circadian rhythms, regulated by clock genes, are important for maintaining physiological balance in tissues.
In a mouse model, disrupted circadian rhythms led to increased bone loss and heightened inflammatory responses.
Knocking down PER2 in human periodontal ligament cells resulted in elevated levels of pro-inflammatory cytokines IL-1β and IL-6.
PER2 knockout mice showed increased bone mass compared to normal mice, suggesting a complex role in bone regulation.
The PER2/miR-21 pathway was found to regulate bone health, affecting both inflammatory and non-inflammatory conditions.
Local application of miR-21 agomir enhanced bone recovery after ligature removal, pointing to its potential in treating periodontitis.

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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.

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Circadian disruption accelerates the progression of experimental periodontitis via PER2/miR-21-mediated inflammatory and osteogenic dysregulation

Abstract

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