Tooth extraction in mice administered zoledronate increases inflammatory cytokine levels and promotes osteonecrosis of the jaw
Tooth extraction in mice administered zoledronate increases inflammatory cytokine levels and promotes osteonecrosis of the jaw
复制标题
唑来膦酸盐致小鼠拔牙增加炎性细胞因子水平并促进颌骨坏死
DOI：
10.1007/s00774-020-01174-2
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发表时间：
2020-11-17
影响因子：
3.3
通讯作者：
Miyamoto, Takeshi
中科院分区：
文献类型：
--
作者：
Soma, Tomoya;Iwasaki, Ryotaro;Miyamoto, Takeshi
颌骨骨坏死（ONJ）发生后，侵入性牙科治疗往往会对患者的日常生活活动产生不利影响。在侵入性牙科治疗前长期给予强效抗骨吸收剂（如双膦酸盐）被认为是ONJ风险因素;然而，ONJ发展的病理机制仍不清楚。材料和方法我们开发了ONJ小鼠模型，其中在用双膦酸盐唑来膦酸盐治疗期间拔牙。结果在拔牙部位的颌骨中观察到骨细胞凋亡诱导，导致空骨陷窝的形成，但在同一小鼠的其他骨中未观察到。我们还观察到唑来膦酸治疗小鼠拔牙部位颌骨中炎症细胞因子水平升高，如TNF α、IL-6和IL-1。我们还报道了唑来膦酸盐或牙龈卟啉单胞菌（一种口腔细菌）提取物的体外治疗可促进破骨细胞祖细胞中炎性细胞因子的表达。我们证明，基因靶向TNF α，IL-6或IL-1或治疗与依那西普，TNF α抑制剂，或针对IL-6的中和抗体可以拮抗ONJ的发展所造成的联合拔牙和唑来膦酸治疗。总之，在双膦酸盐治疗下，侵入性牙科治疗诱导的细胞因子风暴促进ONJ的发展，由于炎症性前列腺素产生细胞的水平升高。我们的工作确定了可能用于预防ONJ的新靶点。
Introduction Osteonecrosis of the jaw (ONJ) occurring after invasive dental treatment often adversely affects patients' activities of daily living. Long-term administration of strong anti-bone resorptive agents such as bisphosphonates prior to invasive dental treatment is considered an ONJ risk factor; however, pathological mechanisms underlying ONJ development remain unclear. Materials and Methods We developed an ONJ mouse model in which a tooth is extracted during treatment with the bisphosphonate zoledronate. Results We observed induction of apoptosis in osteocytes, resulting in formation of empty lacunae in jaw bones at sites of tooth extraction but not in other bones of the same mice. We also observed elevated levels of inflammatory cytokines such as TNF alpha, IL-6 and IL-1 in jaw bone at the extraction site relative to other sites in zoledronate-treated mice. We also report that treatment in vitro with either zoledronate or an extract from Porphyromonas gingivalis, an oral bacteria, promotes expression of inflammatory cytokines in osteoclast progenitor cells. We demonstrate that gene-targeting of either TNF alpha, IL-6 or IL-1 or treatment with etanercept, a TNF alpha inhibitor, or a neutralizing antibody against IL-6 can antagonize ONJ development caused by combined tooth extraction and zoledronate treatment. Conclusions Taken together, the cytokine storm induced by invasive dental treatment under bisphosphonate treatment promotes ONJ development due to elevated levels of inflammatory cytokine-producing cells. Our work identifies novel targets potentially useful to prevent ONJ.