Osteoclast-Derived Exosomes Promote The Occurrence And Development Of MRONJ

The treatment and prevention of medication-related osteonecrosis of the jaw (MRONJ) is a challenge. It is crucial to study the mechanism of MRONJ to carry out precise prevention and treatment. Osteoclast-derived exosomes were extracted and explore its role in cell migration, osteogenesis, angiogenesis and the mechanism in MRONJ in vitro and in vivo. Six-week-old female C57BL/6 mice were randomly divided into four groups: a blank control group (Ctrl), an exosome blank control group (EXO-ctrl), an exosome zoledronic acid treatment group (EXO-za), and a zoledronic acid group (ZA). Osteoclast-derived exosomes could be soaked up by human umbilical vein endothelial cells (HUVECs) and osteoblasts. The cell migration, osteogenesis, angiogenesis decreased in EXO-za and ZA group. The VEGFR2 mRNA and protein expression levels decreased, while the Caspase9 and Notch1-Hes1/Hey mRNA and protein expression levels increased. In vivo, the EXO-za group had decreased trabecular volume, number, and thickness of bone trabeculae and increased trabecular separation in the extraction sockets. Alkaline phosphatase and anti-tartaric acid phosphatase activities were decreased, and the number of H type vessels was decreased in EXO-za group. ZA may contribute to MRONJ by affecting the exocytotic components produced by osteoclasts, through the VEGFR2-Caspase9 and the Notch1-Hes1/Hey signaling pathways.