Regulatory Mechanism of ERKs Pathway on Orthodontic Force Signal Transduction and Osteogenic Differentiation

Objectives: This study aimed to investigate the role of the extracellular signal-regulated kinases (ERKs) signaling pathway in orthodontic force-induced mechanotransduction and osteogenic differentiation, and explore its potential crosstalk with signal transducer and activator of transcription 3 (STAT3), whose regulatory mechanism remains unclear. Materials and Methods: In vitro, MC3T3-E1 preosteoblasts were exposed to cyclic tensile strain (2000 μstrain, 0.5 Hz, 4 h) with or without the specific ERKs inhibitor SCH772984. In vivo, a mouse orthodontic tooth movement (OTM) model was established with 4 g force, and SCH772984 was locally injected into periodontal tissues. Pathway protein expression, osteogenic marker levels, tooth movement distance, and bone microarchitecture were analyzed. Results: Mechanical strain significantly activated ERKs and STAT3 phosphorylation and upregulated key osteogenic markers (Runx2, OSX, OPN, ALP) in vitro; these effects were inhibited by SCH772984 except for COL1. In vivo, orthodontic force-induced alveolar bone remodeling and OTM, with osteogenic markers predominantly elevated on the tension side. SCH772984 treatment suppressed ERKs activation and reduced tooth movement by ~40% (all P <0.05). Conclusions: The ERKs pathway is a critical mediator of orthodontic force-induced alveolar bone remodeling and OTM, functioning partially through STAT3. These findings establish the ERKs/STAT3 axis as a promising therapeutic target for accelerating orthodontic treatment.