Osteonecrosis of the Jaw Developed in Mice

Background: The pathological mechanism of osteonecrosis of the jaw (ONJ) is unknown. Results: Mouse ONJ-like lesions exhibited epithelial hyperplasia associated with T cells of mouse or human origin. Conclusion: T cells may modify the oral disease phenotypes of ONJ. Significance: ONJ pathogenesis may involve multiple mechanisms separately leading to the development of osteonecrosis or oral epithelial abnormality. Osteonecrosis of the jaw (ONJ), an uncommon co-morbidity in patients treated with bisphosphonates (BP), occurs in the segment of jawbone interfacing oral mucosa. This study aimed to investigate a role of oral mucosal barrier T cells in the pathogenesis of ONJ. Female C57Bl/6J (B6) mice received a bolus zoledronate intravenous injection (ZOL, 540 g/kg), and their maxillary left first molars were extracted 1 week later. ZOLtreated mice (WT ZOL) delayed oral wound healing with patent open wounds 4 weeks after tooth extraction with characteristic oral epithelial hyperplasia. T cells appeared within the tooth extraction site and hyperplastic epithelium in WT ZOL mice. In ZOL-treated T cell null (Tcrd / ZOL) mice, the tooth extraction open wound progressively closed; however, histological ONJ-like lesions were identified in 75 and 60% of WT ZOL and Tcrd / ZOL mice, respectively. Although the bone exposure phenotype of ONJ was predominantly observed in WT ZOL mice, Tcrd / ZOL mice developed the pustule/fistula disease phenotype. We further addressed the role of T cells from human peripheral blood (h- T cells). When co-cultured with ZOL-pretreated human osteoclasts in vitro, h- T cells exhibited rapid expansion and robust IFN- secretion. When h- T cells were injected into ZOL-treated immunodeficient (Rag2 / ZOL) mice, the oral epithelial hyperplasia developed. However, Rag2 / ZOL mice did not develop osteonecrosis. The results indicate that T cells are unlikely to influence the core osteonecrosis mechanism; however, they may serve as a critical modifier contributing to the different oral mucosal disease variations of ONJ.