破骨细胞中更高水平的调控因子 NFATc1 和 BCL6 在双膦酸盐治疗相关下颌骨坏死中的表达：与放射性骨坏死和骨髓炎的比较。
Osteoclastic expression of higher-level regulators NFATc1 and BCL6 in medication-related osteonecrosis of the jaw secondary to bisphosphonate therapy: a comparison with osteoradionecrosis and osteomyelitis.
机构信息
Department of Oral and Maxillofacial Surgery, Friedrich-Alexander University Erlangen-Nürnberg, Glückstraße 11, 91054, Erlangen, Germany.
Department of Nephropathology, Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
出版信息
J Transl Med. 2019 Mar 4;17(1):69. doi: 10.1186/s12967-019-1819-1.
BACKGROUND
With an increasing indication spectrum of antiresorptive drugs, the medication-related osteonecrosis of the jaw secondary to bisphosphonate therapy [MRONJ (BP)] is continuously gaining clinical relevance. Impaired osteoclast function, accompanied by altered cell morphology and expression of osteoclastic effector proteins, contributes to the pathogenesis of MRONJ (BP). However, the underlying regulatory mechanisms at a transcriptional level are unaddressed so far. These mechanisms are crucial to the development of disease-characteristic osteoclastic anomalies, that contribute to the pathogenesis of MRONJ (BP). NFATc1 is considered a master upstream osteoclastic activator, whereas BCL6 acts as osteoclastic suppressor. The present study aimed to elucidate the NFATc1 and BCL6 mediated osteoclastic regulation and activity in MRONJ (BP) compared to osteoradionecrosis (ORN) and osteomyelitis (OM) and normal jaw bone.
METHODS
Formalin-fixed jaw bone specimens from 70 patients [MRONJ (BP) n = 30; OM: n = 15, ORN: n = 15, control: n = 10] were analyzed retrospectively for osteoclast expression of NFATc1 and BCL6. The specimens were processed for H&E staining and immunohistochemistry. The histological sections were digitalized and analyzed by virtual microscopy.
RESULTS
Osteoclastic expression of NFATc1 and BCL6 was significantly higher in MRONJ (BP) specimens compared to OM and control specimens. NFATc1 and BCL6 labeling indices revealed no significant differences between MRONJ (BP) and ORN. The ratio of nuclear BCL6+ osteoclasts to cytoplasmic BCL6+ osteoclasts revealed significantly higher values for MRONJ (BP) specimens compared to OM and controls.
CONCLUSION
This study displays that osteoclasts in MRONJ (BP) tissues feature increased expression of the higher-level regulators, paradoxically of both NFATc1 and BCL6. These observations can help to explain the genesis of morphologically altered and resorptive inactive osteoclasts in MRONJ (BP) tissues by outlining the transcriptional regulation of the pathomechanically relevant osteoclastic effector proteins. Furthermore, they strengthen the etiological delineation of MRONJ (BP) from OM and extend the osteoclast profiles of MRONJ (BP), OM and ORN and thus could lead to a better histopathological differentiation that can improve treatment decision and motivate new therapeutic concepts.
背景
随着抗吸收药物的适应证范围不断扩大，双膦酸盐治疗相关的下颌骨坏死（MRONJ（BP））的药物相关性不断增加。破骨细胞功能受损，伴随着细胞形态和破骨细胞效应蛋白表达的改变，导致 MRONJ（BP）的发病机制。然而，到目前为止，尚不清楚转录水平的潜在调节机制。这些机制对于发展具有疾病特征的破骨细胞异常至关重要，这有助于 MRONJ（BP）的发病机制。NFATc1 被认为是破骨细胞的主要上游激活物，而 BCL6 则作为破骨细胞的抑制物。本研究旨在阐明 NFATc1 和 BCL6 在 MRONJ（BP）与放射性骨坏死（ORN）和骨髓炎（OM）和正常颌骨中的破骨细胞调节和活性。
方法
回顾性分析 70 例患者的福尔马林固定颌骨标本[MRONJ（BP）n=30；OM：n=15，ORN：n=15，对照：n=10]，分析 NFATc1 和 BCL6 在破骨细胞中的表达。对标本进行 H&E 染色和免疫组织化学染色。对组织切片进行数字化并通过虚拟显微镜进行分析。
结果
与 OM 和对照标本相比，MRONJ（BP）标本中 NFATc1 和 BCL6 的破骨细胞表达显著升高。NFATc1 和 BCL6 标记指数显示 MRONJ（BP）与 ORN 之间无显著差异。核 BCL6+破骨细胞与胞浆 BCL6+破骨细胞的比值显示 MRONJ（BP）标本明显高于 OM 和对照。
结论
本研究表明，MRONJ（BP）组织中的破骨细胞表达高水平调节剂 NFATc1 和 BCL6 增加。这些观察结果可以帮助解释 MRONJ（BP）组织中形态改变和吸收活性降低的破骨细胞的发生，概述与病理生理相关的破骨细胞效应蛋白的转录调节。此外，它们加强了 MRONJ（BP）与 OM 的病因学区分，并扩展了 MRONJ（BP）、OM 和 ORN 的破骨细胞谱，从而可以实现更好的组织病理学区分，从而改善治疗决策并激发新的治疗概念。
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