Department of Oral and Maxillofacial Surgery, University Hospital Tuebingen, Osianderstr 2-8, 72076, Tübingen, Germany.
J Craniomaxillofac Surg. 2019 Sep;47(9):1464-1474. doi: 10.1016/j.jcms.2019.06.004. Epub 2019 Jun 8.
This study investigated the effects of bisphosphonates and denosumab on human gingival fibroblasts (HGFs) that could influence inflammation, wound healing, and angiogenesis in medication-related osteonecrosis of the jaw (MRONJ).
A real-time in vitro assay was performed on HGFs with and without the addition of bacterial lipopolysaccharide and a mononuclear cell co-culture to observe the effects of zoledronate, ibandronate, alendronate, clodronate, denosumab, and combinations of zoledronate and denosumab at varied concentrations. A wound healing assay was performed, and gene and protein expression was analyzed for inflammatory, angiogenic, and osteoclastogenic cytokines and mediators including interleukin (IL)-1β, IL-6, tumor necrosis factor alpha (TNFα), IL-8, vascular endothelial growth factor (VEGF), RANKL, and osteoprotegerin.
Higher concentrations of antiresorptives resulted in impaired wound healing and HGF death, which also occurred without mechanical damage. These effects were increased with bacterial lipopolysaccharide and mononuclear cells. Increased levels of IL-1β, TNFα, IL-8, VEGF, osteoprotegerin, and decreased levels of IL-6 were observed.
Antiresorptive exposure was associated with HGF death and delayed wound healing, which could be attributed to an elevated inflammatory response and immune dysfunction contributing to MRONJ development. There was no evidence of anti-angiogenic effects. Our experiments present the first results of denosumab with HGFs.
本研究探讨了双膦酸盐和地舒单抗对人牙龈成纤维细胞（HGFs）的影响，这些影响可能会影响药物相关性颌骨骨坏死（MRONJ）中的炎症、伤口愈合和血管生成。
在加入细菌脂多糖和单核细胞共培养的情况下，对 HGFs 进行实时体外检测，以观察唑来膦酸、伊班膦酸、阿仑膦酸、氯膦酸、地舒单抗以及唑来膦酸和地舒单抗的不同浓度组合的作用。进行伤口愈合检测，并分析炎症、血管生成和破骨细胞生成细胞因子和介质的基因和蛋白表达，包括白细胞介素（IL）-1β、IL-6、肿瘤坏死因子α（TNFα）、IL-8、血管内皮生长因子（VEGF）、RANKL 和骨保护素。
更高浓度的抗吸收剂会导致伤口愈合受损和 HGF 死亡，即使没有机械损伤也会发生这种情况。这些影响随着细菌脂多糖和单核细胞的增加而增加。观察到 IL-1β、TNFα、IL-8、VEGF、骨保护素水平升高，IL-6 水平降低。
抗吸收剂暴露与 HGF 死亡和伤口愈合延迟有关，这可能归因于炎症反应和免疫功能障碍的增加，导致 MRONJ 的发展。没有证据表明有抗血管生成作用。我们的实验首次提供了地舒单抗与 HGFs 作用的结果。
