Osteoclast-derived exosomes promote medication-related osteonecrosis of the jaw by delivering glycoRNA to disrupt the blood-lymphatic vascular network.

BACKGROUND/PURPOSE: Medication-related osteonecrosis of the jaw (MRONJ) is a metabolic disorder of the jaw characterized by bone necrosis. Its pathogenesis remains unclear, and elucidating the underlying mechanisms and pathological changes is essential for addressing the clinical challenge of refractory jaw necrosis in MRONJ. Glycosylated RNA (glycoRNA), a recently identified class of small RNAs modified by glycosylation, plays important roles in intercellular communication, signal transduction, and autoimmunity; however, its role in the onset and progression of MRONJ has not yet been investigated. MATERIALS AND METHODS: Exosomes derived from zoledronate-induced osteoclasts (OCZA-Exosomes) were isolated by ultracentrifugation. GlycoRNA was visualized using Ac4ManNAz metabolic labeling combined with Northern blot analysis. Scratch assays, Transwell migration assays, tube-formation assays, EdU staining, and TUNEL staining were performed to evaluate the effects of OCZA-Exosomes on the proliferation, migration, and tube-forming capacity of human umbilical vein endothelial cells (HUVECs) and human lymphatic endothelial cells (HLECs). In MRONJ model rats, the impact of OCZA -Exosomes on jaw necrotic lesions was further assessed. RESULTS: GlycoRNA was shown to undergo intercellular transfer via exosomes. In vitro, OCZA- Exosomes inhibited the proliferation, migration, and tube-forming abilities of HUVECs and HLECs, and induced apoptosis. In MRONJ model rats, local injection of OCZA-Exosomes into the tooth extraction sockets disrupted the blood-lymphatic vascular network within the jaw tissue and accelerated the progression of jaw necrosis. CONCLUSION: These findings reveal a previously unrecognized mechanism by which zoledronate contributes to MRONJ: exosomes-mediated intercellular transfer of glycoRNA disrupts the blood-lymphatic vascular network and promotes jaw necrosis.