Department of Oral and Cranio-Maxillofacial Surgery, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.
Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nürnberg (CCC ER-EMN), Erlangen, Germany.
Front Immunol. 2023 May 24;14:1204188. doi: 10.3389/fimmu.2023.1204188. eCollection 2023.
Medication-related osteonecrosis occurs exclusively in the jaw bones. However, the exact pathogenesis of medication-related osteonecrosis of the jaw (MRONJ) and the unique predisposition of the jaw bones have not been elucidated, making its treatment a challenge. Recent evidence indicates that macrophages might play a pivotal role in MRONJ pathogenesis. The aim of the present study was to compare the macrophage populations between the craniofacial and extracranial skeleton and to investigate the changes induced by zoledronate (Zol) application and surgical interventions.
An experiment was performed. 120 wistar rats were randomized to 4 groups (G1, G2, G3, G4). G1 served as an untreated control group. G2 and G4 received Zol injections for 8 weeks. Afterwards, the right lower molar of the animals from G3 and G4 was extracted and the right tibia osteotomized followed by osteosynthesis. Tissue samples were taken from the extraction socket and the tibia fracture at fixed time points. Immunohistochemistry was conducted to determine the labeling indexes of CD68 and CD163 macrophages.
Comparing the mandible and the tibia, we observed a significantly higher number of macrophages and a heightened pro-inflammatory environment in the mandible compared to the tibia. Tooth extraction caused an increase of the overall number of macrophages and a shift toward a more pro-inflammatory microenvironment in the mandible. Zol application amplified this effect.
Our results indicate fundamental immunological differences between the jaw bone and the tibia, which might be a reason for the unique predisposition for MRONJ in the jaw bones. The more pro-inflammatory environment after Zol application and tooth extraction might contribute to the pathogenesis of MRONJ. Targeting macrophages might represent an attractive strategy to prevent MRONJ and improve therapy. In addition, our results support the hypothesis of an anti-tumoral and anti-metastatic effect induced by BPs. However, further studies are needed to delineate the mechanisms and specify the contributions of the various macrophage phenotypes.
药物相关性颌骨坏死仅发生于颌骨。然而，药物相关性颌骨坏死（MRONJ）的确切发病机制和颌骨的独特易感性尚未阐明，这使得其治疗具有挑战性。最近的证据表明，巨噬细胞可能在 MRONJ 发病机制中发挥关键作用。本研究旨在比较颅面骨骼和颅外骨骼的巨噬细胞群体，并研究唑来膦酸（Zol）应用和手术干预引起的变化。
进行了一项实验。将 120 只 Wistar 大鼠随机分为 4 组（G1、G2、G3、G4）。G1 作为未处理的对照组。G2 和 G4 接受 Zol 注射 8 周。之后，G3 和 G4 动物的右下磨牙被拔出，右侧胫骨骨折并进行内固定。在固定时间点从拔牙窝和胫骨骨折处采集组织样本。进行免疫组织化学染色以确定 CD68 和 CD163 巨噬细胞的标记指数。
与胫骨相比，我们观察到下颌骨的巨噬细胞数量明显更多，且炎症环境更具炎症性。拔牙导致下颌骨中巨噬细胞总数增加，并向更具炎症性的微环境转变。Zol 的应用放大了这种效应。
我们的结果表明颌骨和胫骨之间存在基本的免疫学差异，这可能是颌骨中 MRONJ 独特易感性的原因。Zol 应用和拔牙后更具炎症性的环境可能有助于 MRONJ 的发病机制。靶向巨噬细胞可能是预防 MRONJ 和改善治疗的一种有吸引力的策略。此外，我们的结果支持 BPs 诱导的抗肿瘤和抗转移作用的假说。然而，需要进一步的研究来阐明机制并确定各种巨噬细胞表型的贡献。
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