Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan.
Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan.
Bone. 2024 Oct;187:117200. doi: 10.1016/j.bone.2024.117200. Epub 2024 Jul 15.
Bone resorption inhibitors, such as bisphosphonates (BP) and denosumab, are frequently used for the management of osteoporosis. Although both drugs reduce the risk of osteoporotic fractures, they are associated with a serious side effect known as medication-related osteonecrosis of the jaw (MRONJ). Sclerostin antibodies (romosozumab) increase bone formation and decrease the risk of osteoporotic fractures: however, their anti-resorptive effect increases ONJ. Thus, this study aimed to elucidate the role of sclerostin deletion in the development of MRONJ.
Sclerostin knockout (Sost) mice were used to confirm the development of ONJ by performing tooth extractions. To confirm the role of sclerostin deficiency in a more ONJ-prone situation, we used the BP-induced ONJ model in combination with severe periodontitis to evaluate the development of ONJ and bone formation in wild-type (WT) and Sost mice. Wound healing assay using gingival fibroblasts with or without sclerostin stimulation and tooth extraction socket healing were evaluated in the WT and Sost mice.
ONJ was not detected in the extraction socket of Sost mice. Moreover, the incidence of ONJ was significantly lower in the Sost mice treated with BP compared to that of the WT mice. Osteogenic proteins, osteocalcin, and runt-related transcription factor 2, were expressed in the bone surface in Sost mice. Recombinant sclerostin inhibited gingival fibroblast migration. The wound healing rate of the extraction socket was faster in Sost mice than in WT mice.
Sclerostin deficiency did not cause ONJ and reduced the risk of developing BP-induced ONJ. Enhanced bone formation and wound healing were observed in the tooth extraction socket. The use of romosozumab (anti-sclerostin antibody) has proven to be safe for surgical procedures of the jaw.
骨吸收抑制剂，如双磷酸盐（BP）和地舒单抗，常用于骨质疏松症的治疗。虽然这两种药物都能降低骨质疏松性骨折的风险，但它们都与一种严重的副作用有关，即药物相关性颌骨坏死（MRONJ）。硬骨素抗体（罗莫佐umab）可增加骨形成并降低骨质疏松性骨折的风险：然而，其抗吸收作用会增加 ONJ。因此，本研究旨在阐明硬骨素缺失在 MRONJ 发病机制中的作用。
使用硬骨素敲除（Sost）小鼠通过拔牙来确认 ONJ 的发生。为了确认硬骨素缺乏在更易发生 ONJ 的情况下的作用，我们使用 BP 诱导的 ONJ 模型结合严重牙周炎来评估野生型（WT）和 Sost 小鼠中 ONJ 的发生和骨形成。在 WT 和 Sost 小鼠中评估了用或不用硬骨素刺激的牙龈成纤维细胞的伤口愈合试验以及拔牙窝愈合。
Sost 小鼠拔牙窝中未检测到 ONJ。此外，与 WT 小鼠相比，BP 治疗的 Sost 小鼠 ONJ 的发生率显著降低。骨形成蛋白、骨钙素和 runt 相关转录因子 2 在 Sost 小鼠的骨表面表达。重组硬骨素抑制牙龈成纤维细胞迁移。与 WT 小鼠相比，Sost 小鼠拔牙窝的愈合速度更快。
硬骨素缺乏不会导致 ONJ，并降低了发生 BP 诱导的 ONJ 的风险。在拔牙窝中观察到增强的骨形成和伤口愈合。罗莫佐umab（抗硬骨素抗体）已被证明可安全用于颌骨手术。
