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首页> 外文期刊>Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research >RANKL inhibitors induce osteonecrosis of the jaw in mice with periapical disease
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RANKL inhibitors induce osteonecrosis of the jaw in mice with periapical disease

机译：RANKL抑制剂诱导根尖周炎小鼠下颌骨坏死

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Antiresorptive medications are essential in treating diseases of pathologic osteoclastic bone resorption, including bone cancer and osteoporosis. Bisphosphonates (BPs) are the most commonly used antiresorptives in clinical practice. Although inhibition of bone resorption is important in regulating unwanted malignant and metabolic osteolysis, BP treatment is associated with potential side effects, including osteonecrosis of the jaws (ONJ). Recently, non-BP antiresorptive medications targeting osteoclastic function and differentiation, such as denosumab, have entered the clinical arena. Denosumab treatment results in a similar rate of ONJ as BPs. Animal models of ONJ, using high-dose BP treatment in combination with tooth extraction or dental disease, provide valuable tools and insight in exploring ONJ pathophysiology. However, the ability of other antiresorptives to induce ONJ-like lesions in animal models has not been explored. Such studies would be beneficial in providing support for the role of osteoclast inhibition in ONJ pathogenesis versus a direct BP effect on oral tissues. Here, we tested the ability of the receptor activator of NF-κB ligand (RANKL) inhibitors RANK-Fc (composed of the extracellular domain of RANK fused to the fragment crystallizable [Fc] portion of immunoglobulin G [IgG]) and OPG-Fc (composed of the RANKL-binding domains of osteoprotegerin [OPG] linked to the Fc portion of IgG) to induce ONJ in mice in the presence of periapical disease, but in the absence of dental extractions. We demonstrate radiographic evidence of ONJ in RANK-Fc-treated and OPG-Fc-treated mice, including inhibition of bone loss, increased bone density, lamina dura thickening, and periosteal bone deposition. These findings closely resembled the radiographic appearance of an ONJ patient on denosumab treatment. Histologic examination revealed that RANK-Fc treatment and OPG-Fc treatment resulted in absence of osteoclasts, periosteal bone formation, empty osteocytic lacunae, osteonecrosis, and bone exposure. In conclusion, we have successfully induced ONJ in mice with periapical disease, using potent osteoclast inhibitors other than BPs. Our findings, coupled with ONJ animal models using high-dose BPs, suggest that osteoclast inhibition is pivotal to the pathogenesis of ONJ.
机译：抗吸收药物对于治疗病理性破骨细胞骨吸收疾病（包括骨癌和骨质疏松症）至关重要。双膦酸盐（BPs）是临床实践中最常用的抗吸收剂。尽管抑制骨吸收对于调节有害的恶性和代谢性骨溶解很重要，但BP治疗与潜在的副作用相关，包括颌骨坏死（ONJ）。最近，靶向破骨细胞功能和分化的非BP抗吸收药物，如denosumab，已进入临床领域。地诺单抗治疗导致的ONJ发生率与BP相似。 ONJ的动物模型采用大剂量BP治疗与拔牙或牙齿疾病相结合，为探索ONJ病理生理学提供了有价值的工具和见识。但是，尚未探索其他抗再吸收剂在动物模型中诱导ONJ样病变的能力。这样的研究将有利于提供对破骨细胞抑制作用在ONJ发病机理中的作用的支持，而不是对口腔组织的直接BP作用的支持。在这里，我们测试了NF-κB配体（RANKL）抑制剂RANK-Fc（由RANK的胞外域融合到免疫球蛋白G [IgG]的可结晶[Fc]部分的片段组成）的受体激活剂的能力，以及OPG-Fc （由骨保护素[OPG]的RANKL结合域组成，与IgG的Fc部分相连）在有根尖周疾病但没有牙提取物的情况下诱导小鼠ONJ。我们证明了RANK-Fc治疗和OPG-Fc治疗的小鼠中ONJ的放射学证据，包括抑制骨丢失，增加骨密度，椎板硬脑膜增厚和骨膜骨沉积。这些发现与denosumab治疗的ONJ患者的影像学表现非常相似。组织学检查显示，RANK-Fc治疗和OPG-Fc治疗导致没有破骨细胞，骨膜骨形成，空的骨细胞性腔隙，骨坏死和骨暴露。总之，我们已经使用除BPs以外的有效破骨细胞抑制剂成功诱导了根尖周病小鼠的ONJ。我们的发现，再加上使用大剂量BP的ONJ动物模型，表明破骨细胞抑制作用是ONJ发病机理的关键。

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