Osteoclast-Derived Exosomes Promote MRONJ via the VEGFR2-Caspase9 and Notch1-Hes1/Hey Signaling Pathways.

OBJECTIVE

To elucidate the mechanism of medication-related osteonecrosis of the jaw (MRONJ), which is challenging to prevent and treat, to facilitate the development of precise prevention and treatment strategies.

MATERIALS AND

METHODS

Osteoclast-derived exosomes were extracted and their roles in cell migration, osteogenesis, angiogenesis, and the mechanism of MRONJ were investigated.

RESULTS

Osteoclast-derived exosomes were taken up by human umbilical vein endothelial cells and osteoblasts. Cell migration and vascularization decreased in cells treated with zoledronic acid (ZA)-induced exosomes. VEGFR2 mRNA and protein expression decreased, while Caspase9 mRNA and protein expression increased. The migration and osteogenic differentiation of osteoblasts induced by exosomes from ZA-treated osteoclasts decreased, and the mRNA and protein expression of Notch1-Hes1/Hey increased. In vivo, ZA-treated osteoclast-derived exosomes caused decreased trabecular volume, number, and thickness and increased trabecular separation in the extraction sockets. Alkaline phosphatase and tartrate-resistant acid phosphatase activities decreased, and the number of H-type vessels decreased in the ZA-treated group.

CONCLUSION

ZA may contribute to MRONJ by affecting the exocytotic components produced by osteoclasts through the VEGFR2-Caspase9 and Notch1-Hes1/Hey signaling pathways.