The Shapiro Family Laboratory of Viral Oncology and Aging Research, University of California, Los Angeles, Los Angeles, California.
The Shapiro Family Laboratory of Viral Oncology and Aging Research, University of California, Los Angeles, Los Angeles, California; School of Dentistry, Dankook University, Cheonan, Republic of Korea.
Am J Pathol. 2018 Oct;188(10):2318-2327. doi: 10.1016/j.ajpath.2018.06.019. Epub 2018 Jul 27.
Medication-related osteonecrosis of the jaw (MRONJ) is a rare but detrimental intraoral lesion that predominantly occurs in patients with long-term use of antiresorptive agents, such as bisphosphonate and denosumab, a human anti-receptor activator of NF-κB ligand (RANKL) monoclonal antibody (Ab). Surgical intervention, such as tooth extraction, is a known risk factor for MRONJ, which is often performed to eliminate preexiting pathologic inflammatory conditions, such as periodontal diseases. Nonetheless, it remains unknown whether pre-existing periodontal disease condition exacerbates, or removal of such condition ameliorates, MRONJ development after tooth extraction. In this study, we combined the ligature-induced periodontitis and the tooth extraction mouse models under the administration of zoledronic acid (ZOL) or anti-RANKL Ab, and provide experimental evidence that a pre-existing pathologic inflammatory condition exacerbates MRONJ development after tooth extraction in mice. Under ZOL administration, tooth extraction alone induced ONJ lesions; however, extraction of a ligature-placed tooth further exacerbated ONJ development. When the ligature was removed and the inflammatory condition was deescalated, ONJ development was ameliorated. Anti-RANKL Ab administration resulted in similar outcomes. Interestingly, unlike ZOL-administered mice, anti-RANKL Ab-administered mice exhibited complete absence of osteoclasts, suggesting that physical presence of osteoclasts is not directly involved in ONJ development. Collectively, our study demonstrated that periodontal disease is a functionally linked risk factor that predisposes ONJ development after tooth extraction in the presence of bisphosphonate and denosumab.
药物相关性下颌骨坏死（MRONJ）是一种罕见但有害的口腔内病变，主要发生在长期使用抗吸收剂（如双膦酸盐和地舒单抗，一种人抗核因子-κB 配体（RANKL）单克隆抗体（Ab））的患者中。手术干预，如拔牙，是 MRONJ 的已知危险因素，通常用于消除先前存在的病理性炎症情况，如牙周病。然而，目前尚不清楚先前存在的牙周病状况是否会加重，或者去除这种状况是否会改善拔牙后 MRONJ 的发展。在这项研究中，我们结合了结扎诱导的牙周炎和在唑来膦酸（ZOL）或抗 RANKL Ab 给药下拔牙的小鼠模型，并提供了实验证据表明，先前存在的病理性炎症状况会加重小鼠拔牙后 MRONJ 的发展。在 ZOL 给药下，单独拔牙会引起 ONJ 病变；然而，结扎牙的拔除会进一步加重 ONJ 的发展。当结扎物被移除且炎症情况得到缓解时，ONJ 的发展得到改善。抗 RANKL Ab 的给药也会产生类似的结果。有趣的是，与 ZOL 给药的小鼠不同，抗 RANKL Ab 给药的小鼠完全没有破骨细胞，这表明破骨细胞的物理存在并不直接参与 ONJ 的发展。总的来说，我们的研究表明，牙周病是一种功能相关的危险因素，在存在双膦酸盐和地舒单抗的情况下，会导致拔牙后发生 ONJ。
