Gefitinib Facilitates Bone Fracture Healing via Inhibition of the EGFR Pathway and Counteracting SOX9-driven Bone Metabolic Reprogramming.

BACKGROUND/AIM: To investigate the role of epidermal growth factor receptor (EGFR) inhibition in enhancing bone fracture healing by modulating box transcription factor 9 (SOX9) and bone metabolism. MATERIALS AND METHODS: A rat femoral fracture model was used. Techniques included histological analysis, X-ray scoring, micro-computed tomography, immunohistochemistry, and biomechanical testing. Serum markers were analyzed with enzyme-linked immunosorbent assay, while quantitative real-time polymerase chain reaction and western blotting assessed molecular pathways. Metabolic changes were measured using a Seahorse analyzer. An EGFR inhibitor, gefitinib, was used to examine its impact on periosteal stem cell differentiation and metabolism. RESULTS: EGFR inhibition improved bone callus formation and quality, increased cartilage callus, and upregulated bone formation markers. Gefitinib enhanced oxidative phosphorylation and fatty acid oxidation, counteracting negative effects from lipid-reduced serum on osteoblastic differentiation of periosteal stem cell. SOX9 overexpression reduced the benefits of EGFR inhibition. CONCLUSION: Gefitinib enhances bone fracture healing by modulating lipid metabolism through SOX9, suggesting its potential as a therapeutic agent for improving fracture outcomes.