Yang Xiaojie, Xu Xing, Chen Jun, Wang Qing, Wang Guangfei, Ai Xuemin, Wang Xu, Pan Jinsong
Department of Stomatology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cell Death Discov. 2020 Jun 11;6:47. doi: 10.1038/s41420-020-0273-4. eCollection 2020.
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出现有害副作用的风险，如双膦酸盐相关的颌骨坏死（BRONJ）。BRONJ的发生与炎症有关，但其病理生理学仍不清楚。在此，我们研究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显著增加了巨噬细胞中白细胞介素1β的表达以及Gasdermin D的切割，这两者均由半胱天冬酶1激活。Kdm6a和Kdm6b的抑制剂有力地消除了Zol增强的巨噬细胞白细胞介素1β的合成和分泌。当在体内对Kdm6a和Kdm6b进行药理抑制时，唑来膦酸治疗的小鼠牙槽窝愈合不良和炎症反应得到改善。综上所述，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。
