Department of Applied Prosthodontics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8588, Japan.
Department of Applied Prosthodontics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8588, Japan.
Bone. 2023 Dec;177:116899. doi: 10.1016/j.bone.2023.116899. Epub 2023 Sep 12.
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a potentially intractable disease with no definitive pathophysiology and no treatment and prevention strategies. This study aimed to investigate whether time-selective depletion of macrophages worsens BRONJ-like lesions in mice. A murine model of high-prevalence BRONJ-like lesions in combination with zoledronate/chemotherapeutic drug administration and tooth extraction was created according to the methods of our previous studies. Daily intra-oral submucosal administration of clodronate-loaded liposomes, which temporarily depletes systemic macrophages, was performed immediately after tooth extraction. Spleens, femora, tibiae, and maxillae were dissected 2 weeks after extraction to evaluate BRONJ-like lesions and systemic conditions by micro-computed tomography analysis, histomorphometric and immunofluorescent analyses, and serum chemistry with ELISA. Depletion of macrophages significantly decreased the numbers of local and systemic macrophages and osteoclasts on the bone surface, which markedly worsened osseous healing, with increased necrotic bone and empty lacunae in the existing alveolar bone and newly formed bone in the extraction sockets, and soft tissue healing, with decreased collagen production and increased infiltration of polymorphonuclear cells. Interestingly, the depletion of macrophages significantly shifted macrophage polarization to M1 macrophages through an increase in F4/80CD38 M1 macrophages and a decrease in F4/80CD163 M2 macrophages, with decreases in the total number of F4/80 macrophages. These data demonstrated that severe inhibition of osteoclasts in bone tissue and polarization shifting of macrophages in soft tissue are essential factors associated with BRONJ.
颌骨骨坏死（BRONJ）是一种潜在的难治性疾病，目前尚无明确的病理生理学机制，也没有治疗和预防策略。本研究旨在探讨选择性耗竭巨噬细胞是否会加重小鼠 BRONJ 样病变。根据我们之前的研究方法，建立了一种高发性 BRONJ 样病变的小鼠模型，该模型结合唑来膦酸/化疗药物给药和拔牙。拔牙后立即进行氯膦酸盐负载的脂质体的口腔黏膜下每日局部给药，这种脂质体可以暂时耗竭系统性巨噬细胞。拔牙后 2 周，解剖脾脏、股骨、胫骨和上颌骨，通过 micro-CT 分析、组织形态计量学和免疫荧光分析以及 ELISA 血清化学评估 BRONJ 样病变和全身状况。巨噬细胞耗竭显著减少了骨表面的局部和全身巨噬细胞和破骨细胞数量，这明显恶化了骨愈合，增加了坏死骨和现有牙槽骨中的空陷窝以及拔牙窝中新形成的骨，也恶化了软组织愈合，胶原生成减少，多形核细胞浸润增加。有趣的是，巨噬细胞的耗竭通过增加 F4/80CD38 M1 巨噬细胞和减少 F4/80CD163 M2 巨噬细胞，显著将巨噬细胞极化转向 M1 巨噬细胞，同时 F4/80 巨噬细胞总数减少。这些数据表明，骨组织中破骨细胞的严重抑制和软组织中巨噬细胞的极化转变是与 BRONJ 相关的重要因素。
