Osteonecrosis of the Jaw Developed in Mice: DISEASE VARIANTS REGULATED BY gammadelta T CELLS IN ORAL MUCOSAL BARRIER IMMUNITY.

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 gammadelta T cells in the pathogenesis of ONJ. Female C57Bl/6J (B6) mice received a bolus zoledronate intravenous injection (ZOL, 540 mug/kg), and their maxillary left first molars were extracted 1 week later. ZOL-treated mice (WT ZOL) delayed oral wound healing with patent open wounds 4 weeks after tooth extraction with characteristic oral epithelial hyperplasia. gammadelta T cells appeared within the tooth extraction site and hyperplastic epithelium in WT ZOL mice. In ZOL-treated gammadelta 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 gammadelta T cells from human peripheral blood (h-gammadelta T cells). When co-cultured with ZOL-pretreated human osteoclasts in vitro, h-gammadelta T cells exhibited rapid expansion and robust IFN-gamma secretion. When h-gammadelta 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 gammadelta 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.