Rattanawonsakul Krit, Bullock George, Bolt Robert, Claeyssens Frederik, Atkins Simon, Hearnden Vanessa
Department of Materials Science and Engineering, The University of Sheffield, Sheffield, United Kingdom.
School of Clinical Dentistry, The University of Sheffield, Sheffield, United Kingdom.
Front Oral Health. 2022 Jun 20;3:892615. doi: 10.3389/froh.2022.892615. eCollection 2022.
Medication-related osteonecrosis of the jaw (MRONJ) is an often-severe complication found in patients receiving bisphosphonates in the management of Paget's, osteoporosis and metastatic bone cancer. Mucosal breakdown with bone exposure is a primary clinical presentation of MRONJ linked to the inhibitory effect of nitrogen-containing bisphosphonates (N-BP) on the mevalonate pathway. Geranylgeraniol (GGOH) has demonstrated a rescue effect on N-BP-treated osteoclasts but the biological effects on oral soft tissues and cells remain unclear. This study aimed to determine whether GGOH could prevent bisphosphonate induced toxicity to oral mucosa cells . Primary oral fibroblasts and keratinocytes were exposed to different GGOH concentrations or GGOH in combination with two nitrogen-containing bisphosphonates, zoledronic acid (ZA) or pamidronic acid (PA), for 72 h. The metabolic activity of each cell type was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. GGOH without bisphosphonates significantly reduced the metabolic activity of oral mucosa cells. Fibroblasts treated with GGOH and ZA in combination showed a slight increase in metabolic status compared to fibroblasts treated with ZA alone, however this positive effect was not observed in keratinocytes. In the presence of PA, GGOH was unable to increase the metabolic activity of either cell type. These findings demonstrate that GGOH is toxic to oral mucosa cells and that GGOH was not able to prevent bisphosphonate induced toxicity. These data show that GGOH does not have therapeutic potential for bisphosphonate-induced soft tissue toxicity in MRONJ and the use of GGOH as an MRONJ treatment should be strongly reconsidered.
药物相关性颌骨坏死（MRONJ）是接受双膦酸盐治疗佩吉特氏病、骨质疏松症和转移性骨癌患者中常见的严重并发症。黏膜破损伴骨暴露是MRONJ的主要临床表现，与含氮双膦酸盐（N-BP）对甲羟戊酸途径的抑制作用有关。香叶基香叶醇（GGOH）已显示出对N-BP处理的破骨细胞有挽救作用，但对口腔软组织和细胞的生物学作用仍不清楚。本研究旨在确定GGOH是否能预防双膦酸盐诱导的口腔黏膜细胞毒性。将原代口腔成纤维细胞和角质形成细胞暴露于不同浓度的GGOH或GGOH与两种含氮双膦酸盐唑来膦酸（ZA）或帕米膦酸（PA）的组合中72小时。使用3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四氮唑溴盐（MTT）法测量每种细胞类型的代谢活性。不含双膦酸盐的GGOH显著降低了口腔黏膜细胞的代谢活性。与单独用ZA处理的成纤维细胞相比，联合用GGOH和ZA处理的成纤维细胞代谢状态略有增加，然而在角质形成细胞中未观察到这种积极作用。在PA存在的情况下，GGOH不能增加任何一种细胞类型的代谢活性。这些发现表明GGOH对口腔黏膜细胞有毒性，并且GGOH不能预防双膦酸盐诱导的毒性。这些数据表明GGOH对MRONJ中双膦酸盐诱导的软组织毒性没有治疗潜力，应强烈重新考虑将GGOH用作MRONJ的治疗方法。
