Regulating Macrophage Polarization Promotes BMSC Homing For MRONJ Prevention

Bisphosphonates, widely used for osteoporosis and bone metastases, may cause medication-related osteonecrosis of the jaw (MRONJ). This study investigates the role of macrophage polarization and bone marrow-derived mesenchymal stem cell (BMSC) recruitment in MRONJ pathogenesis and explores strategies to prevent its development. A C57BL/6J mouse model of MRONJ was established via zoledronic acid (ZA) administration and tooth extraction. Macrophage polarization trends were analyzed using histological staining and in vitro RAW264.7 cell polarization models. CXCL16 expression in extraction sockets and its effects on BMSC migration were evaluated via ELISA, PCR, and co-culture assays. RNA sequencing and Western blotting identified signaling pathways modulated by CXCL16. The preventive effects of M2 macrophage polarization were tested using local IL-4 injection in ZA-treated mice. All animal experimental protocols were approved by the Ethics Committee of West China Hospital of Stomatology (WCHSIRB-D-2023-611). ZA induced MRONJ-like features, including delayed socket healing and reduced angiogenesis. M1 macrophages dominated in MRONJ sockets, suppressing BMSC migration, while M2 macrophages promoted BMSC recruitment via CXCL16 secretion. CXCL16 activated the PI3K/AKT pathway in BMSCs, enhancing their migration and angiogenic capacity. Local IL-4 treatment improved socket healing and BMSC recruitment in high-risk MRONJ mice. Bisphosphonates disrupt macrophage polarization balance, exacerbating inflammation and inhibiting BMSC recruitment, leading to MRONJ. Modulating macrophage polarization toward M2 enhances CXCL16/CXCR6/PI3K/AKT signaling, promoting BMSC chemotaxis and angiogenesis, thereby preventing MRONJ development.