Macrophage Polarization during MRONJ Development in Mice.

Journal of dental research Pub Date : 2024-08-01 Epub Date: 2024-08-05 DOI:10.1177/00220345241258990
A Soundia, N Elzakra, D Hadaya, I Gkouveris, O Bezouglaia, S Dry, T Aghaloo, S Tetradis
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Abstract

Macrophages are important regulators of bone remodeling, and M1 polarization is observed in the setting of medication-related osteonecrosis of the jaws (MRONJ). Here, we characterize the phenotype of macrophages during early stages of MRONJ development in zoledronate (ZA)-treated mice with periodontal disease and explore the role of rosiglitazone, a drug that has been reported to lower the M1/M2 macrophage ratio, in MRONJ burden. Mice received ZA, and experimental periodontal disease (EPD) was induced around their second left maxillary molar. The mice were euthanized 1, 2, or 4 wk later. Micro-computed tomography and histologic and immunohistochemical analyses were carried out. In a separate experiment, mice were treated with ZA in the absence or presence of rosiglitazone, EPD was induced for 5 wk, and the MRONJ burden was assessed. An M1 predilection was noted in ZA versus vehicle (Veh) mice at 1, 2, or 4 wk after ligature placement. M1 cells were found to be positive for MMP-13, and their presence coincided with disruption of the surrounding collagen network in ZA mice. Rosiglitazone caused a reversal in the M1/M2 polarization in Veh and ZA mice. Rosiglitazone did not cause significant radiographic changes 5 wk after EPD in Veh or ZA animals. Importantly, percentage osteonecrosis and bone exposure were decreased in the rosiglitazone-treated versus nontreated ZA sites 5 wk after EPD. Our data point to an important role of M1 macrophage polarization with an overexpression of MMP-13 in the early phases of MRONJ development and provide insight into the use of interventional approaches promoting an M2 phenotype as a preventative means to alleviate MRONJ burden.

小鼠 MRONJ 发育过程中的巨噬细胞分化
巨噬细胞是骨重塑的重要调节因子,在药物相关性颌骨坏死(MRONJ)的情况下可观察到巨噬细胞的M1极化。在这里,我们描述了唑来膦酸钠(ZA)治疗的牙周病小鼠在MRONJ发展早期阶段巨噬细胞的表型,并探讨了罗格列酮(一种据报道能降低M1/M2巨噬细胞比例的药物)在MRONJ负担中的作用。小鼠接受ZA治疗,并在左侧第二颗上颌臼齿周围诱发实验性牙周病(EPD)。小鼠在1、2或4周后被安乐死。对小鼠进行显微计算机断层扫描、组织学和免疫组化分析。在另一项实验中,小鼠在无罗格列酮或有罗格列酮的情况下接受ZA治疗,诱导EPD 5周,并评估MRONJ负担。在结扎后1、2或4周时,ZA与载体(Veh)小鼠相比,发现M1偏好。发现 M1 细胞对 MMP-13 呈阳性反应,它们的存在与ZA 小鼠周围胶原网络的破坏相吻合。罗格列酮导致Veh和ZA小鼠的M1/M2极化发生逆转。罗格列酮不会导致Veh和ZA小鼠在EPD 5周后出现明显的放射学变化。重要的是,在EPD 5周后,罗格列酮处理的ZA部位与未处理的ZA部位相比,骨坏死和骨暴露的百分比均有所下降。我们的数据表明,M1巨噬细胞极化与MMP-13的过度表达在MRONJ发展的早期阶段起着重要作用,并为使用促进M2表型的干预方法作为减轻MRONJ负担的预防手段提供了启示。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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