Gene expression profiles in the articular cartilage of juvenile rats receiving the quinolone antibacterial agent ofloxacin.
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 2h post-dose; cell death- and inflammatory response-related genes at 4 and 8h post-dose; basic-leucine zipper transcription factor and stress response-related genes at 8 and 24h post-dose; stress response-, proteolysis- and glycoprotein-related genes at 24h 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.
Medicinal Safety Research Laboratories, Daiichi Sankyo Co Ltd, Tokyo, Japan. goto.koichi.s7@daiichisankyo.co.jp
Koichi
K
Goto
Koichi
K
Yabe
Takami
T
Suzuki
Kiyoshi
K
Takasuna
Toshimasa
T
Jindo
Sunao
S
Manabe
D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D017403:In Situ Hybridization; D008297:Male; D015242:Ofloxacin / Q000633:toxicity*; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000900:Anti-Bacterial Agents; D012313:RNA; D015242:Ofloxacin