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Ofloxacin induces apoptosis in microencapsulated juvenile rabbit chondrocytes by caspase-8-dependent mitochondrial

Zhiguo Sheng1, Xiaojuan Cao, Shuangqing Peng

  • 1National Beijing Center for Drug Safety Evaluation and Research, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, China.

Toxicology and Applied Pharmacology
|October 27, 2007
PubMed

Insights

Quinolone-induced arthropathy in young animals is a concern. Ofloxacin triggers chondrocyte apoptosis via the caspase-8-dependent mitochondrial pathway, impacting joint health.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pharmacology

Background:

  • Quinolones (QNs) can cause arthropathy in juvenile animals, limiting pediatric use.
  • The precise mechanism of QN-induced chondrocyte apoptosis remains unclear.
  • Previous work showed ofloxacin induces apoptosis by disrupting beta 1 integrin and inactivating ERK/MAPK.

Purpose of the Study:

  • To elucidate the mechanisms of ofloxacin-induced apoptosis in juvenile rabbit joint chondrocytes.
  • To investigate the role of specific caspases in ofloxacin-induced chondrocyte apoptosis.
  • To determine the involvement of the mitochondrial pathway in this process.

Main Methods:

  • Utilized specific caspase-9 (zLEHD-fmk) and caspase-8 (zIETD-fmk) inhibitors.
  • Assessed apoptosis using fluorescent dye staining, enzyme activity assays, and immunoblotting.
  • Measured cytochrome c translocation, mitochondrial membrane potential, and levels of apoptosis-related proteins (Bax, tBid, p53).

Main Results:

  • Both caspase inhibitors attenuated ofloxacin-induced apoptosis and caspase-3 activation.
  • Caspase-8 inhibition blocked cytochrome c release and mitochondrial dysfunction.
  • Ofloxacin increased pro-apoptotic proteins Bax, tBid, and p53.
  • Caspase-8 inhibition primarily affected caspase-9 and -3 activation, suggesting a caspase-8-dependent mitochondrial pathway.

Conclusions:

  • The caspase-8-dependent mitochondrial pathway is the primary mechanism for ofloxacin-induced apoptosis in juvenile rabbit chondrocytes.
  • These findings contribute to understanding quinolone toxicity and developing safer therapeutic strategies.
  • Targeting the caspase-8 pathway may mitigate quinolone-induced arthropathy.

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