Force threshold-dependent modulation of root resorption via the Nrf2/Keap1/p62 antioxidant pathway during orthodontic tooth movement

Introduction: Orthodontically induced root resorption (OIRR) is a frequent yet poorly understood complication of orthodontic treatment. Emerging evidence links oxidative stress to mechanical loading. However, the regulation of redox homeostasis in periodontal tissues under varying force magnitudes remains unclear. Nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of antioxidant defense, modulates inflammation and bone remodeling, but its force-dependent role in OIRR is undefined.

Methods: Periodontal ligament fibroblasts were subjected to graded compressive forces (0-2 g/cm²) in vitro to assess Nrf2/kelch-like ECH-associated protein 1 (Keap1)/sequestosome 1 (p62) pathway activation and downstream inflammatory and osteoclastic responses. Genetic and pharmacologic modulation of Nrf2 signaling was performed. In vivo, a murine orthodontic tooth movement model applying light (10 g) and heavy (40 g) forces was used to evaluate Nrf2 function in periodontal remodeling and root resorption.

Results: Nrf2 displayed threshold-dependent regulation. Moderate force (≤1.5 g/cm²) activated the Nrf2/HO-1 pathway, preserving redox balance and limiting inflammation, whereas excessive force (2 g/cm²) led to Nrf2 saturation, resulting in ROS accumulation, amplified inflammation, and enhanced osteoclastogenesis. Keap1 knockdown restored antioxidant capacity and reduced inflammation, whereas p62 knockdown impaired Nrf2 activation and aggravated tissue injury. In vivo, heavy force induced sustained interleukin-1β expression and severe root resorption, intensified by Nrf2 inhibition.

Conclusions: Force-dependent saturation of the Nrf2/Keap1/p62 pathway acts as a molecular switch linking oxidative stress and inflammation in OIRR. Nrf2 serves as a mechanosensitive regulator of periodontal homeostasis and a potential therapeutic target to prevent root resorption.