Department of Oral and Maxillofacial-Head & Neck Oncology, Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Stomatology, Shanghai Eighth People's Hospital, Shanghai, China.
Appl Biochem Biotechnol. 2024 Oct;196(10):7362-7374. doi: 10.1007/s12010-024-04859-w. Epub 2024 Mar 25.
Long-term administration of bisphosphonates can lead to a significant side effect known as bisphosphonate-related osteonecrosis of the jaw (BRONJ). Although macrophage-mediated inflammation has been established as an important factor in BRONJ, the underlying mechanism remains elusive. In the current study, the roles of endoplasmic reticulum (ER) stress in zoledronic acid (ZOL)-induced inflammation were analyzed in macrophages, and the regulatory mechanism of ER stress activation was next investigated. An in vitro model of BRONJ was established by treating RAW264.7 cells with ZOL. The activation of ER stress was analyzed by western blotting and transmission electron microscopy, and inflammation was assessed by quantitative real-time PCR and enzyme-linked immunosorbent assay. ER stress was significantly activated in ZOL-treated macrophages, and inhibition of ER stress by TUDCA, an ER stress inhibitor, suppressed ZOL-induced inflammation in macrophages. Mechanistically, phosphodiesterase 4B (PDE4B) was significantly increased in ZOL-treated macrophages. Forced expression of PDE4B promoted ER stress and inflammation, whereas PDE4B knockdown decreased ZOL-induced ER stress and inflammation in macrophages. More importantly, PDE4B inhibitor could improve ZOL-induced BRONJ in vivo. These data suggest that ZOL accelerates ER stress-mediated inflammation in BRONJ by increasing PDE4B expression. PDE4B inhibition may represent a potential therapeutic strategy for BRONJ. Subsequent research should concentrate on formulating medications that selectively target PDE4B, thereby mitigating the risk of BRONJ in patients undergoing bisphosphonate treatment.
长期使用双膦酸盐可导致一种称为双膦酸盐相关性颌骨坏死（BRONJ）的显著副作用。尽管巨噬细胞介导的炎症已被确立为 BRONJ 的一个重要因素，但潜在机制仍难以捉摸。在本研究中，分析了内质网（ER）应激在唑来膦酸（ZOL）诱导的巨噬细胞炎症中的作用，并进一步研究了 ER 应激激活的调节机制。通过用 ZOL 处理 RAW264.7 细胞建立 BRONJ 的体外模型。通过 Western blot 和透射电子显微镜分析 ER 应激的激活，通过定量实时 PCR 和酶联免疫吸附试验评估炎症。ZOL 处理的巨噬细胞中 ER 应激明显被激活，内质网应激抑制剂 TUDCA 抑制 ER 应激可抑制巨噬细胞中 ZOL 诱导的炎症。从机制上讲，磷酸二酯酶 4B（PDE4B）在 ZOL 处理的巨噬细胞中显著增加。PDE4B 的强制表达促进了 ER 应激和炎症，而 PDE4B 的敲低则降低了巨噬细胞中 ZOL 诱导的 ER 应激和炎症。更重要的是，PDE4B 抑制剂可改善体内 ZOL 诱导的 BRONJ。这些数据表明，ZOL 通过增加 PDE4B 的表达加速 BRONJ 中 ER 应激介导的炎症。PDE4B 抑制可能代表 BRONJ 的一种潜在治疗策略。后续研究应集中于制定选择性靶向 PDE4B 的药物，从而降低接受双膦酸盐治疗的患者发生 BRONJ 的风险。
