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.

中文翻译：

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小鼠 MRONJ 发育过程中的巨噬细胞极化


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） 的情况下观察到 M1 极化。在这里，我们表征了唑来膦酸盐 （ZA） 处理的牙周病小鼠 MRONJ 发育早期巨噬细胞的表型，并探讨了罗格列酮的作用，罗格列酮是一种据报道可降低 M1/M2 巨噬细胞比率的药物，在 MRONJ 负荷中的作用。小鼠接受 ZA，并在其第二左上颌磨牙周围诱导实验性牙周病 （EPD）。小鼠在 1 、 2 或 4 周后被安乐死。进行了显微计算机断层扫描以及组织学和免疫组织化学分析。在单独的实验中，在不存在或存在罗格列酮的情况下用 ZA 处理小鼠，诱导 EPD 5 周，并评估 MRONJ 负荷。在结扎放置后 1 、 2 或 4 周，ZA 与赋形物 （Veh） 小鼠相比，观察到 M1 偏好。发现 M1 细胞对 MMP-13 呈阳性，它们的存在与 ZA 小鼠周围胶原蛋白网络的破坏相吻合。罗格列酮导致 Veh 和 ZA 小鼠的 M1/M2 极化发生逆转。罗格列酮在 Veh 或 ZA 动物 EPD 后 5 周未引起显着的放射学变化。重要的是，EPD 后 5 周，罗格列酮治疗与未治疗 ZA 部位的骨坏死百分比和骨暴露百分比降低。我们的数据指出 MMP-13 过表达的 M1 巨噬细胞极化在 MRONJ 发育的早期阶段起着重要作用，并提供了关于使用促进 M2 表型的干预方法作为减轻 MRONJ 负担的预防手段的见解。