Gene expression profiles in the articular cartilage of juvenile rats receiving the quinolone antibacterial agent ofloxacin
Gene expression profiles in the articular cartilage of juvenile rats receiving the quinolone antibacterial agent ofloxacin
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DOI：
10.1016/j.tox.2008.05.005
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发表时间：
2008-07-30
期刊：
影响因子：
4.5
通讯作者：
Manabe, Sunao
中科院分区：
文献类型：
--
作者：
Goto, Koichi;Yabe, Koichi;Manabe, Sunao
喹诺酮类抗菌剂广泛用于抗菌化疗。然而，据报道它们会诱发幼年动物关节病，但其机制尚未阐明。在本研究中，为了研究喹诺酮氧氟沙星 (OFLX) 软骨毒性的分子细节，对 3 周龄的雄性幼年 Sprague-Dawley 大鼠以 900 mg/kg 的剂量水平口服一次。然后在给药后2、4、8和24小时分析股骨远端关节软骨中的基因表达谱。在GeneChip分析中，OFLX处理组中134个基因探针的表达显示出统计学上的显着差异，与对照组相比至少有1.5倍的差异。其中，细胞内信号级联和应激反应相关基因在给药后2小时发生变化；给药后 4 小时和 8 小时的细胞死亡和炎症反应相关基因；给药后 8 小时和 24 小时的碱性亮氨酸拉链转录因子和应激反应相关基因；给药后 24 小时应激反应、蛋白水解和糖蛋白相关基因。在定量实时逆转录聚合酶链反应分析中，观察到关节中 Dusp1（细胞内信号级联相关基因）、Tnfrsf12a（细胞死亡相关基因）、Ptgs2、Fos（炎症反应相关基因）、Mt1a、Plaur（应激反应相关基因）和 Mmp3（蛋白水解相关基因）上调，以及 Sstr1 和 Has2（糖蛋白相关基因）下调，且呈剂量依赖性。用 100、300 和 900 mg/kg OFLX 处理的幼年大鼠的软骨。通过原位杂交还发现软骨损伤周围的软骨细胞中 Tnfrsf12a、Ptgs2、Plaur 和 Mmp3 的表达。总之，我们的结果表明，细胞死亡、炎症反应、应激反应和蛋白水解相关基因上调产生的细胞因子、趋化因子和/或蛋白酶在 OFLX 诱导的幼年大鼠软骨毒性的发生中发挥重要作用。 (C) 2008 Elsevier Ireland Ltd. 保留所有权利。
Quinolone antibacterial agents are extensively utilized in antimicrobial chemotherapy. However, they have been reported to induce arthropathy in juvenile animals, and the mechanism has not been clarified. In the present study, to investigate the molecular details of the chondrotoxicity of the quinolone ofloxacin (OFLX), it was orally administered by gavage at a dose level of 900 mg/kg once to male juvenile Sprague-Dawley rats, 3 weeks of age. Then gene expression profiles in the articular cartilage of the distal femur were analyzed at 2. 4, 8 and 24h post-dose. In the GeneChip analysis, the expression of 134 gene probes in the OFLX-treated group showed statistically significant differences with at least 1.5-fold difference from the control. Among them, intracellular signaling cascade- and stress response-related genes changed at 2 h post-dose; cell death- and inflammatory response-related genes at 4 and 8 h post-dose; basic-leucine zipper transcription factor and stress response-related genes at 8 and 24 h post-dose; stress response-, proteolysis- and glycoprotein-related genes at 24 h post-dose. In a quantitative real-time reverse transcription-polymerase chain reaction analysis, up-regulated Dusp1 (intracellular signaling cascade-related gene), Tnfrsf12a (cell death-related gene), Ptgs2, Fos (inflammatory response-related genes), Mt1a, Plaur (stress response-related genes) and Mmp3 (proteolysis-related gene) and down-regulated Sstr1 and Has2 (glycoprotein-related genes) were observed with dose dependency in the articular cartilage of juvenile rats treated with OFLX at 100, 300 and 900 mg/kg. The expression of Tnfrsf12a, Ptgs2, Plaur and Mmp3 was also noted in chondrocytes around the cartilage lesions by in situ hybridization. In conclusion, our results suggest that cytokines, chemokines and/or proteases produced by up-regulation of cell death-, inflammatory response-, stress response- and proteolysis-related genes play a important role in the onset of OFLX-induced chondrotoxicity in juvenile rats. (C) 2008 Elsevier Ireland Ltd. All rights reserved.