Zoledronic acid delays wound healing of the tooth extraction socket, inhibits oral epithelial cell migration, and promotes proliferation and adhesion to hydroxyapatite of oral bacteria, without causing osteonecrosis of the jaw, in mice
Zoledronic acid delays wound healing of the tooth extraction socket, inhibits oral epithelial cell migration, and promotes proliferation and adhesion to hydroxyapatite of oral bacteria, without causing osteonecrosis of the jaw, in mice
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DOI：
10.1007/s00774-009-0128-9
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发表时间：
2010-03-01
影响因子：
3.3
通讯作者：
Yoneda, Toshiyuki
中科院分区：
文献类型：
--
作者：
Kobayashi, Yasuyoshi;Hiraga, Toru;Yoneda, Toshiyuki
含氮双膦酸盐如唑来膦酸（ZOL）和帕米膦酸已被广泛且成功地用于治疗患有骨转移和/或高钙血症的癌症患者。最近越来越多的报告表明，接受这些双膦酸盐治疗的癌症患者在牙科治疗（包括拔牙）后偶尔会出现与双膦酸盐相关的颌骨坏死（BRONJ）。然而，迄今为止，人们对 BRONJ 的发病机制知之甚少。在这里，为了了解 BRONJ 的潜在发病机制，我们使用小鼠拔牙模型检查了 ZOL 对拔牙槽伤口愈合的影响。组织形态计量学分析显示，与对照组小鼠相比，ZOL 治疗小鼠的新骨量和牙槽窝中的血管数量显着减少。与这些结果一致，ZOL 显着抑制体内血管内皮生长因子诱导的血管生成以及培养物中内皮细胞的增殖，且呈剂量依赖性。相比之下，依替膦酸（一种不含氮的双膦酸盐）对牙槽窝中的成骨和血管生成没有影响。 ZOL 还抑制口腔上皮细胞的迁移，这是牙槽闭合的关键步骤。此外，ZOL还能促进变形链球菌对羟基磷灰石的粘附以及健康个体口腔细菌的增殖，表明ZOL可能会增加细菌感染。总之，我们的数据表明 ZOL 通过抑制成骨和血管生成来延迟拔牙槽的伤口愈合。我们的数据还表明 ZOL 可以改变口腔细菌的行为。 ZOL 的这些作用可能与 BRONJ 的发病机制有关。
Nitrogen-containing bisphosphonates such as zoledronic acid (ZOL) and pamidronate have been widely and successfully used for the treatment of cancer patients with bone metastases and/or hypercalcemia. Accumulating recent reports have shown that cancer patients who have received these bisphosphonates occasionally manifest bisphosphonate-related osteonecrosis of the jaw (BRONJ) following dental treatments, including tooth extraction. However, little is known about the pathogenesis of BRONJ to date. Here, to understand the underlying pathogenesis of BRONJ, we examined the effects of ZOL on wound healing of the tooth extraction socket using a mouse tooth extraction model. Histomorphometrical analysis revealed that the amount of new bone and the numbers of blood vessels in the socket were significantly decreased in ZOL-treated mice compared to control mice. Consistent with these results, ZOL significantly inhibited angiogenesis induced by vascular endothelial growth factor in vivo and the proliferation of endothelial cells in culture in a dose-dependent manner. In contrast, etidronate, a non-nitrogen-containing bisphosphonate, showed no effects on osteogenesis and angiogenesis in the socket. ZOL also suppressed the migration of oral epithelial cells, which is a crucial step for tooth socket closure. In addition, ZOL promoted the adherence of Streptococcus mutans to hydroxyapatite and the proliferation of oral bacteria obtained from healthy individuals, suggesting that ZOL may increase the bacterial infection. In conclusion, our data suggest that ZOL delays wound healing of the tooth extraction socket by inhibiting osteogenesis and angiogenesis. Our data also suggest that ZOL alters oral bacterial behaviors. These actions of ZOL may be relevant to the pathogenesis of BRONJ.