Kobayashi Hideyuki, Fujita Ryo, Hiratsuka Shigeto, Shimizu Tomohiro, Sato Dai, Hamano Hiroki, Iwasaki Norimasa, Takahata Masahiko
Department of Orthopaedic Surgery, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
J Orthop Res. 2022 Mar;40(3):614-623. doi: 10.1002/jor.25102. Epub 2021 May 28.
Osteomyelitis is characterized by progressive inflammatory bone destruction accompanied by severe pain and disability. However, with the exception of antibiotic therapies, there is no established therapy to protect the bone from infectious osteolysis. The anti-receptor activator of nuclear factor-kB ligand (RANKL) monoclonal antibody (anti-RANKL Ab) is a potential drug based on its proven effectiveness in preventing joint bone erosion in rheumatoid arthritis; however, the efficacy and adverse effects of anti-RANKL Ab in osteomyelitis remain to be investigated. In this study, we investigated the effects of anti-mouse RANKL Ab on acute osteomyelitis and compared them with those of zoledronic acid (ZA) using a murine model. Mice were inoculated with bioluminescent Staphylococcus aureus (Xen 29) on their left femur and then treated with ZA, anti-RANKL Ab, or phosphate-buffered saline as control. A 21-day longitudinal observational study using microcomputed tomography showed that both anti-RANKL Ab and ZA had an osteoprotective effect against infectious osteolysis. However, it was also demonstrated through bioluminescence imaging that ZA delayed the spontaneous reduction of bacterial load and through histology that it increased the amount of necrotic bone, while anti-RANKL Ab did not. Findings from histopathological and in vitro studies suggest that an intense inflammatory response around the necrotic bone could induce osteoclasts in a RANKL-independent manner, leading to the removal of necrotic bone, even after administration of the anti-RANKL Ab therapy. Collectively, anti-RANKL Ab may exert an osteoprotective effect without hampering the removal of the necrotic bone, which serves as a nidus for infection in osteomyelitis.
骨髓炎的特征是进行性炎症性骨破坏，并伴有严重疼痛和功能障碍。然而，除了抗生素治疗外，尚无成熟的疗法可保护骨骼免受感染性骨溶解。核因子-κB配体（RANKL）单克隆抗体（抗RANKL抗体）是一种潜在药物，因为它在预防类风湿性关节炎关节骨侵蚀方面已证实有效；然而，抗RANKL抗体在骨髓炎中的疗效和不良反应仍有待研究。在本研究中，我们使用小鼠模型研究了抗小鼠RANKL抗体对急性骨髓炎的影响，并将其与唑来膦酸（ZA）的影响进行了比较。在小鼠左股骨接种生物发光金黄色葡萄球菌（Xen 29），然后用ZA、抗RANKL抗体或磷酸盐缓冲盐水作为对照进行治疗。一项使用微型计算机断层扫描的为期21天的纵向观察研究表明，抗RANKL抗体和ZA对感染性骨溶解均具有骨保护作用。然而，生物发光成像也显示ZA延迟了细菌载量的自发降低，组织学显示它增加了坏死骨的量，而抗RANKL抗体则没有。组织病理学和体外研究结果表明，坏死骨周围强烈的炎症反应可能以RANKL非依赖的方式诱导破骨细胞，导致坏死骨的清除，即使在给予抗RANKL抗体治疗后也是如此。总体而言，抗RANKL抗体可能发挥骨保护作用，而不妨碍坏死骨的清除，坏死骨是骨髓炎感染的病灶。
