| Summary: | Introduction: Osteoradionecrosis (ORN) of the mandible is a serious complication following radiation therapy for malignancies of the head and neck. Radiation-induced fibrosis (RIF) is a new theory that accounts for the damage to normal tissues after radiotherapy, and the radiation-induced fibroatrophic mechanism includes the free-radical formation, endothelial dysfunction, inflammation, microvascular thrombosis, fibrosis and remodeling, and finally bone and tissue necrosis. The Hypothesis: Previous studies revealed that transforming growth factor-β1 (TGF-β1) is the master switch cytokine responsible for the regulation of fibroblast proliferation and differentiation that result in RIF. Among the targets of TGF-β1, connective tissue growth factor (CTGF) is a downstream mediator through the Smad3/4 pathway and plays an important role in connective tissue homeostasis and fibroblast proliferation. Studies have proved that the TGF-β1/Smad/CTGF signaling pathway is involved in the RIF of soft tissues, so the authors put forward a hypothesis that the TGF-β1/Smad/CTGF axis is also the main pathway in RIF of ORN. Evaluation of the Hypothesis: The validation of our hypothesis may provide new insights for better understanding the pathogenesis of ORN and open new perspectives for anti-fibrotic therapies, and pioneer novel approaches to treat ORN.
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