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.

中文翻译：

---

唑来膦酸和香叶基香叶醇对原代人破骨细胞中血管生成基因表达的影响。

与双膦酸盐有关的颌骨坏死（BRONJ）是与双膦酸盐治疗相关的严重并发症。唑来膦酸（ZA）是一种常用的双膦酸盐，因为它在增加骨密度和减少骨骼事件方面有效，并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）取代甲羟戊酸途径，以确定ZA对原代人破骨细胞中血管生成基因表达的影响。通过使用外周血单核细胞分离从三名患者的外周血单核细胞产生破骨细胞培养物。通过相差显微镜，抗酒石酸酸性磷酸酶染色和凹坑分析对这些细胞进行表型分析。发现原代破骨细胞以很高的水平表达许多关键的血管生成分子。使用PCR阵列确定了84种人类血管生成因子的基因表达水平。响应ZA的三个具有显着倍数调节（FR）的基因如下：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的共同添加导致这三个基因以及CCL2，TGFBR1，ENG和CXCL1显着下调。GGOH逆转了ZA诱导的基因改变，可能为BRONJ提供有希望的治疗方法。香叶基香叶醇与ZA的共同添加导致这三个基因以及CCL2，TGFBR1，ENG和CXCL1显着下调。GGOH逆转了ZA诱导的基因改变，可能为BRONJ提供有希望的治疗方法。香叶基香叶醇与ZA的共同添加导致这三个基因以及CCL2，TGFBR1，ENG和CXCL1显着下调。GGOH逆转了ZA诱导的基因改变，可能为BRONJ提供有希望的治疗方法。