Long-term administration of nitrogen-containing bisphosphonates increases the risk of detrimental side effects, such as bisphosphonate-related osteonecrosis of the jaw (BRONJ). BRONJ development is associated with inflammation, but its pathophysiology remains unknown. Here, we examined whether histone methylation is responsible for zoledronic acid (Zol)-induced inflammatory responses. We found that Kdm6a and Kdm6b markedly increased interleukin 1β expression and Gasdermin D cleavage, which are both activated by Caspase 1, in macrophages. Inhibitors of Kdm6a and Kdm6b robustly abolished Zol-enhanced interleukin 1β synthesis and secretion from macrophages. When Kdm6a and Kdm6b were pharmacologically inhibited in vivo, poor healing of the alveolar socket and inflammatory responses were ameliorated in Zol-treated mice. Taken together, we showed the pathologic role of Kdm6a and Kdm6b in Zol-promoted inflammatory responses and demonstrated that Kdm6a and Kdm6b are potential therapeutic targets for the treatment of BRONJ.

长期服用含氮双膦酸盐会增加有害副作用的风险，例如双膦酸盐相关的颌骨坏死（BRONJ）。BRONJ 的发育与炎症有关，但其病理生理学仍不清楚。在这里，我们检查了组蛋白甲基化是否与唑来膦酸（Zol）诱导的炎症反应有关。我们发现 Kdm6a 和 Kdm6b 显着增加巨噬细胞中白细胞介素 1β 的表达和 Gasdermin D 的裂解，这两者均由 Caspase 1 激活。Kdm6a 和 Kdm6b 抑制剂可有效消除 Zol 增强的巨噬细胞白细胞介素 1β 的合成和分泌。当 Kdm6a 和 Kdm6b 在体内受到药理抑制时，Zol 治疗的小鼠牙槽窝愈合不良和炎症反应得到改善。总之，我们展示了 Kdm6a 和 Kdm6b 在 Zol 促进的炎症反应中的病理作用，并证明 Kdm6a 和 Kdm6b 是治疗 BRONJ 的潜在治疗靶点。