Zafar Sobia, P Cullinan Mary, K Drummond Bernadette, J Seymour Gregory, E Coates Dawn
Discipline of Paediatric Dentistry, School of Dentistry, The University of Queensland.
Discipline of Periodontics, School of Dentistry, The University of Queensland.
J Oral Sci. 2020;62(1):79-83. doi: 10.2334/josnusd.19-0130.
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious complication associated with bisphosphonate treatment. Zoledronic acid (ZA) is a commonly used bisphosphonate due to its effectiveness in increasing bone density and reducing skeletal events, with evidence that it alters angiogenesis. Replacement of the mevalonate pathway using geranylgeraniol (GGOH) was studied to determine the effects of ZA on angiogenic gene expression in primary human osteoclasts. Osteoclast cultures were generated from peripheral blood mononuclear cells of three patients using the peripheral blood mononuclear cell isolation. These cells were phenotyped by phase-contrast microscopy, tartrate-resistant acid phosphatase staining, and pit assays. Primary osteoclasts were found to express a number of key angiogenic molecules at very high levels. Gene expression levels for 84 human angiogenic factors were determined using PCR arrays. Three genes with significant fold regulation (FR) in response to ZA were as follows: tumor necrosis factor (FR = +2.57, P = 0.050), CXCL9 (FR = +39.48, P = 0.028), and CXCL10 (FR = +18.52, P = 0.0009). The co-addition of geranylgeraniol with ZA resulted in the significant down-regulation of these three genes along with CCL2, TGFBR1, ENG, and CXCL1. GGOH reversed the gene changes induced by ZA and may offer a promising treatment for BRONJ.
双膦酸盐相关的颌骨坏死（BRONJ）是双膦酸盐治疗相关的一种严重并发症。唑来膦酸（ZA）是一种常用的双膦酸盐，因其在增加骨密度和减少骨相关事件方面的有效性，且有证据表明它会改变血管生成。研究了使用香叶基香叶醇（GGOH）替代甲羟戊酸途径，以确定ZA对原代人破骨细胞血管生成基因表达的影响。使用外周血单个核细胞分离法从三名患者的外周血单个核细胞中培养破骨细胞。通过相差显微镜、抗酒石酸酸性磷酸酶染色和陷窝试验对这些细胞进行表型分析。发现原代破骨细胞高水平表达多种关键血管生成分子。使用PCR阵列测定84种人类血管生成因子的基因表达水平。对ZA有显著倍数调节（FR）的三个基因如下：肿瘤坏死因子（FR = +2.57，P = 0.050）、CXCL9（FR = +39.48，P = 0.028）和CXCL10（FR = +18.52，P = 0.0009）。香叶基香叶醇与ZA共同添加导致这三个基因以及CCL2、TGFBR1、ENG和CXCL1显著下调。GGOH逆转了ZA诱导的基因变化，可能为BRONJ提供一种有前景的治疗方法。
