Thiel Yasmin, Ghayor Chafik, Lindhorst Daniel, Essig Harald, Weber Franz, Rücker Martin, Schumann Paul
Department of Oral and Maxillofacial Surgery, University Hospital Zurich, Frauenklinikstrasse 24, CH-8091 Zurich, Switzerland.
Center of Dental Medicine, Oral Biotechnology & Bioengineering, University of Zurich, Plattenstrasse 11, CH-8032 Zurich, Switzerland.
Pathol Res Pract. 2020 Dec;216(12):153245. doi: 10.1016/j.prp.2020.153245. Epub 2020 Oct 9.
Bisphosphonates and denosumab are commonly used antiresorptive therapies in patients with bone metastasis and osteoporosis. Medication-related osteonecrosis of the jaw (MRONJ) is a serious side effect of these drugs, and infection has been recognized as a contributing factor. Current therapeutic options for MRONJ show limited effectiveness, therefore necessitating novel treatment strategies. Bisphosphonates have recently been reported to induce the expression of antimicrobial peptides (AMPs), an inherent component of the immune system. Therefore, the aim of the present study was to investigate and compare the influence of the anti-RANKL antibody denosumab and bisphosphonates on the gene expression of selected AMPs: human α-defensin-1, human α-defensin-3, human β-defensin-1, and human β-defensin-3. Bone specimens were collected from patients with MRONJ who had been treated with bisphosphonates (n = 6) or denosumab (n = 6), and from healthy subjects (n = 6) with no history of treatment with bone metabolism-influencing drugs. Reverse transcription-quantitative polymerase chain reaction was used to quantify the expression levels of selected AMPs. Samples from patients treated with denosumab showed significantly higher mRNA expression of human α-defensin-3 and human β-defensin-3 than those from healthy subjects. This finding is similar to previously described upregulated expression of human defensins in patients with MRONJ after bisphosphonates treatment. This suggests that the elevated expression of defensins may be at least a part of the mechanism underlying the pathogenesis of osteonecrosis induced by antiresorptive therapies, which can serve as a new target for potential treatment of MRONJ.
双膦酸盐和地诺单抗是骨转移和骨质疏松患者常用的抗吸收治疗药物。药物相关性颌骨坏死（MRONJ）是这些药物的一种严重副作用，感染被认为是一个促成因素。目前针对MRONJ的治疗选择效果有限，因此需要新的治疗策略。最近有报道称双膦酸盐可诱导抗菌肽（AMPs）的表达，抗菌肽是免疫系统的固有组成部分。因此，本研究的目的是调查和比较抗RANKL抗体地诺单抗和双膦酸盐对所选AMPs基因表达的影响：人α-防御素-1、人α-防御素-3、人β-防御素-1和人β-防御素-3。从接受过双膦酸盐治疗（n = 6）或地诺单抗治疗（n = 6）的MRONJ患者以及无影响骨代谢药物治疗史的健康受试者（n = 6）中采集骨标本。采用逆转录定量聚合酶链反应来定量所选AMPs的表达水平。接受地诺单抗治疗的患者样本显示人α-防御素-3和人β-防御素-3的mRNA表达明显高于健康受试者。这一发现与先前描述的双膦酸盐治疗后MRONJ患者中人类防御素表达上调相似。这表明防御素表达升高可能至少是抗吸收治疗诱导骨坏死发病机制的一部分，这可作为MRONJ潜在治疗的新靶点。
