Abstract：
OBJECTIVE: 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.
METHODS: Sclerostin knockout (SostΔ26/Δ26) 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 SostΔ26/Δ26 mice. Wound healing assay using gingival fibroblasts with or without sclerostin stimulation and tooth extraction socket healing were evaluated in the WT and SostΔ26/Δ26 mice.
RESULTS: ONJ was not detected in the extraction socket of SostΔ26/Δ26 mice. Moreover, the incidence of ONJ was significantly lower in the SostΔ26/Δ26 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 SostΔ26/Δ26 mice. Recombinant sclerostin inhibited gingival fibroblast migration. The wound healing rate of the extraction socket was faster in SostΔ26/Δ26 mice than in WT mice.
CONCLUSIONS: 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.
METHODS: Sclerostin knockout (SostΔ26/Δ26) 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 SostΔ26/Δ26 mice. Wound healing assay using gingival fibroblasts with or without sclerostin stimulation and tooth extraction socket healing were evaluated in the WT and SostΔ26/Δ26 mice.
RESULTS: ONJ was not detected in the extraction socket of SostΔ26/Δ26 mice. Moreover, the incidence of ONJ was significantly lower in the SostΔ26/Δ26 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 SostΔ26/Δ26 mice. Recombinant sclerostin inhibited gingival fibroblast migration. The wound healing rate of the extraction socket was faster in SostΔ26/Δ26 mice than in WT mice.
CONCLUSIONS: 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.
摘要：
目的：骨吸收抑制剂，例如双膦酸盐（BP）和地诺单抗，经常用于治疗骨质疏松症。虽然这两种药物都能降低骨质疏松性骨折的风险，它们与严重的副作用有关，称为药物相关的颌骨坏死（MRONJ）。硬化蛋白抗体（romosozumab）增加骨形成并降低骨质疏松性骨折的风险：然而，它们的抗再吸收作用增加了ONJ。因此，本研究旨在阐明硬化蛋白缺失在MRONJ发育中的作用。
方法：使用硬化蛋白敲除（SostΔ26/Δ26）小鼠通过进行拔牙来确认ONJ的发展。为了证实硬化素缺乏在更容易发生ONJ的情况下的作用，我们将BP诱导的ONJ模型与重度牙周炎联合使用，以评估野生型（WT）和SostΔ26/Δ26小鼠中ONJ的发育和骨形成。在WT和SostΔ26/Δ26小鼠中评估了使用有或没有硬化蛋白刺激的牙龈成纤维细胞和拔牙窝愈合的伤口愈合测定。
结果：在SostΔ26/Δ26小鼠的拔牙槽内未检测到ONJ。此外，与WT小鼠相比,用BP处理的SostΔ26/Δ26小鼠中ONJ的发生率显著较低。成骨蛋白,骨钙蛋白，和runt相关转录因子2在SostΔ26/Δ26小鼠的骨表面表达。重组硬化蛋白抑制牙龈成纤维细胞迁移。SostΔ26/Δ26小鼠的拔牙槽的伤口愈合速率比WT小鼠快。
结论：硬化素缺乏不会引起ONJ，并降低了发生BP诱导的ONJ的风险。在拔牙槽中观察到增强的骨形成和伤口愈合。romosozumab（抗硬化蛋白抗体）的使用已被证明对于颌骨的外科手术是安全的。
方法：使用硬化蛋白敲除（SostΔ26/Δ26）小鼠通过进行拔牙来确认ONJ的发展。为了证实硬化素缺乏在更容易发生ONJ的情况下的作用，我们将BP诱导的ONJ模型与重度牙周炎联合使用，以评估野生型（WT）和SostΔ26/Δ26小鼠中ONJ的发育和骨形成。在WT和SostΔ26/Δ26小鼠中评估了使用有或没有硬化蛋白刺激的牙龈成纤维细胞和拔牙窝愈合的伤口愈合测定。
结果：在SostΔ26/Δ26小鼠的拔牙槽内未检测到ONJ。此外，与WT小鼠相比,用BP处理的SostΔ26/Δ26小鼠中ONJ的发生率显著较低。成骨蛋白,骨钙蛋白，和runt相关转录因子2在SostΔ26/Δ26小鼠的骨表面表达。重组硬化蛋白抑制牙龈成纤维细胞迁移。SostΔ26/Δ26小鼠的拔牙槽的伤口愈合速率比WT小鼠快。
结论：硬化素缺乏不会引起ONJ，并降低了发生BP诱导的ONJ的风险。在拔牙槽中观察到增强的骨形成和伤口愈合。romosozumab（抗硬化蛋白抗体）的使用已被证明对于颌骨的外科手术是安全的。
