Molecular Mechanism of Ciprofloxacin-Induced Chondrotoxicity in Juvenile Animals

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  • Shinagawa Ayano
    Department of Pediatrics, St. Marianna University School of Medicine
  • Minagawa Kimino
    Department of Pharmacogenomics, St. Marianna University Graduate School of Medicine
  • Nishikawa Hiroyuki
    Institute of Advanced Medical Science, St. Marianna University Graduate School of Medicine
  • Yui Naoko
    Department of Sports Medicine, St. Marianna University School of Medicine
  • Ohnuma Shigeko
    Department of Pathology, St. Marianna University School of Medicine
  • Sasaki Chizuko
    Institute for Ultrastructural Morphology, St. Marianna University Graduate School of Medicine
  • Takagi Masayuki
    Department of Pathology, St. Marianna University School of Medicine
  • Yamamoto Hitoshi
    Department of Pediatrics, St. Marianna University School of Medicine
  • Kumai Toshio
    Department of Pharmacogenomics, St. Marianna University Graduate School of Medicine

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  • 幼若ラットにおけるキノロン系抗菌薬シプロフロキサシンによる関節障害の分子メカニズム

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<p>Quinolone antibacterial agents have been reported to induce articular cartilage damage in juvenile animals, and therefore, their therapeutic use in pediatric and adolescent patients is restricted. However, the exact mechanism of quinolone-induced chondrotoxicity remains unclear. The aim of this study was to investigate the molecular mechanism of chondrotoxicity induced by ciprofloxacin, a second-generation quinolone. Ciprofloxacin (1,200 mg/kg once daily) was orally administered on 10 consecutive days to 3-week-old rats. After treatment, the thickness of the cartilage decreased, and dilated cisternae of rough endoplasmic reticulum were observed. A shotgun proteomics analysis of ciprofloxacin-treated and -untreated rat chondrocytes was subsequently performed. As a result, 78 kD glucose-regulated protein (GRP78), an endoplasmic reticulum (ER) stress-related protein, was identified. To investigate whether ER stress is involved in ciprofloxacin-induced chondrotoxicity, we examined the protein expression of GRP78 and C/EBP homologous protein (CHOP), which is well known to promote cell death. Western blot analysis showed a significant 2.2-fold increase (p < 0.01) in CHOP, but not in GRP78, protein expression in ciprofloxacin-treated rat chondrocytes compared to those in untreated rats. These results suggested that the ciprofloxacin-induced chondrotoxicity was caused by induced ER stress-mediated apoptosis in juvenile rat chondrocytes.</p>

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