Objectives: Transplantation of adipose-derived regenerative cells (ADRCs) have a regenerative effect on bone and have an anti-inflammatory effect on soft tissue. Medication-related osteonecrosis of the jaw (MRONJ) is rarely but severely adverse effect of bisphosphonates and anti-RANKL monoclonal antibody. The aim of this study was to investigate the effects of ADRC transplantation on bisphosphonate/anticancer drug-induced ONJ-like lesions and bone marrow microenvironment.
Materials and Methods: Female C57BL/6J mice were used. Zoledronate (ZA)/cyclophosphamide (CY) were administered for 7 weeks. A single ADRC transplantation was performed just after tooth extraction of first molar at 3 weeks after ZA/CY initiation. Saline was used as control for ADRC therapies. Euthanasia was carried out 2 weeks after tooth extraction. MicroCT scan, Histomorphometry (H-E staining, TRAP staining and trichrome staining), immunohistochemistry (CD31, F4/80 and CD206), and qPCR were performed. Independent t-test was used.
Results: ADRC transplantation promoted both soft and hard tissue wound healing in tooth extraction sockets by increasing new bone formation and decreasing necrotic bone, and by increasing collagen production, blood vessels, M2 macrophages and decreasing inflammatory cells in wounds. ADRC transplantation significantly suppressed the increase of TRAP positive mononuclear cells and detached osteoclasts induced by ZA/CY injection in tooth extraction wounds and bone marrow. Moreover, upregulated stem cell, macrophage and anti-apoptotic gene expressions and suppressed apoptotic gene expressions were noted in bone marrow.
Conclusion: ADRC transplantation via tail vein had local and systemic effects. MRONJ may be correlated with TRAP positive mononuclear cells and detached osteoclasts induced by ZA/CY administration. Promoted tooth extraction socket healing by ADRC therapy might be associated with upregulated macrophages and suppressed cell apoptosis.