Anti-mouse RANKL Antibodies Inhibit Alveolar Bone Destruction in Periodontitis Model Mice
Anti-mouse RANKL Antibodies Inhibit Alveolar Bone Destruction in Periodontitis Model Mice
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DOI：
10.1248/bpb.b18-00026
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发表时间：
2018-04-01
影响因子：
2
通讯作者：
Takami, Masamichi
中科院分区：
文献类型：
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作者：
Kuritani, Miku;Sakai, Nobuhiro;Takami, Masamichi
Denosumab是一种抗骨吸收药物，由靶向核因子κ B配体受体激活剂（RANKL）的完整人单克隆抗体组成，RANKL负责破骨细胞形成。该药物已适用于骨骼疾病，如骨质疏松症和与癌症相关的骨转移，但不用于与牙周炎相关的牙槽骨破坏。在本研究中，我们的目的是澄清狄诺塞单抗是否可以预防模型小鼠中与脂多糖（LPS）诱导的颅骨炎症和实验性牙周炎相关的骨破坏。Denosumab不与小鼠RANKL结合，因此我们使用了抗小鼠单克隆RANKL抗体。我们还研究了另一种抗骨吸收药物唑来膦酸盐（一种含氮双膦酸盐）对骨破坏的抑制作用。将抗RANKL抗体局部给予颅骨区域可抑制LPS诱导的破骨细胞形成和骨破坏，而唑来膦酸盐可抑制骨破坏，但由于其不同的作用机制，不能抑制破骨细胞形成。在牙周炎模型小鼠中，用丝线结扎第二磨牙以诱导炎症，腹腔内给予抗RANKL抗体显著抑制牙槽骨破坏和牙根暴露。另一方面，唑来膦酸盐只能微弱地抑制牙槽骨破坏，不能抑制牙根暴露。这些结果表明，地舒单抗是一种有前途的候选药物，以防止与牙周炎相关的牙槽骨破坏。
Denosumab is an anti-bone resorptive drug consisting of complete human monoclonal antibodies that targets receptor activator of nuclear factor kappa B ligand (RANKL), which is responsible for osteoclast formation. The drug has been adapted for bone diseases, such as osteoporosis and bone metastasis related to cancer, but is not used for alveolar bone destruction related to periodontitis. In the present study, we aimed to clarify whether denosumab prevents bone destruction associated with lipopolysaccharide (LPS)-induced calvaria inflammation and experimental periodontitis in model mice. Denosumab does not bind to mouse RANKL, thus we used anti-mouse monoclonal RANKL antibodies. We also examined the inhibitory effects toward bone destruction of another anti-bone resorptive drug zoledronate, a nitrogen-containing bisphosphonate. Local administration of anti- RANKL antibodies into the calvaria area inhibited LPS-induced osteoclast formation and bone destruction, while zoledronate inhibited bone destruction but not osteoclast formation due to its different action mechanism. In periodontitis model mice, in which the second molars were ligated with a silk suture to induce inflammation, intraperitoneal administration of anti-RANKL antibodies significantly inhibited alveolar bone destruction and tooth root exposure. On the other hand, zoledronate only weakly repressed alveolar bone destruction and failed to inhibit root exposure. These results suggest that denosumab is a promising candidate to prevent alveolar bone destruction associated with periodontitis.