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TOXICOLOGY

Apoptosis in Microencapsulated Juvenile Rabbit Chondrocytes Induced by Ofloxacin: Role Played by ₁-Integrin Receptor

National Beijing Center for Drug Safety Evaluation and Research, Beijing Institute of Pharmacology and Toxicology, Beijing, China (Z.S., S.P., C.W., H.L., Y.W., Q.L., M.L., Y.D., G.H.); and Neuroscience Program, Michigan State University, East Lansing, Michigan (R.K.H.)

Quinolone(s) (QNs) is widely used in infection therapy due to its good antimicrobial characteristics. However, QNs-induced arthropathy of immature animals has led to restrictions on the therapeutic use of these antimicrobial agents. The exact mechanism(s) of QNs-induced chondrotoxicity remain unknown. In the present study, we investigated the possible mechanism of ofloxacin (one typical QNs)-induced injuries of chondrocytes. Juvenile rabbit joint chondrocytes cultured in alginate microspheres were incubated with ofloxacin at concentrations of 0, 2, 5, 10, 20, and 40 µg/ml for up to 96 h. Concentration of 10 µg/ml ofloxacin induced apoptosis of chondrocyte with visible apoptotic signs, including degradation of poly(ADP-ribose) polymerase, caspase-3 activation, and DNA ladder formation. Furthermore, extracellular signal-regulated kinase 1/2 (phospho-ERK1/2) and growth factor receptor-bound protein 2 (Grb2) were significantly reduced, and similar changes were also observed in the ₁-integrin receptor as assessed by immunoblotting. However, the mRNA level of ₁-integrin obtained from reverse transcription-polymerase chain reaction remained unchanged. Results of ₁-integrin immunoprecipitation have also shown that ₁-integrin did not interact with activated intracellular signaling proteins. In addition, ofloxacin did not induce apoptosis and decrease ₁-integrin expression in chondrocytes supplemented with Mg²⁺, and the ofloxacin-induced apoptosis was caspase-8-dependent, inhibition of which did not affect the expression mode of phospho-ERK1/2 and ₁-integrin. Our results demonstrate that ofloxacin affects ₁-integrin receptor functions and the ERK mitogen-activated protein kinase signaling pathway, causing caspase-8-dependent apoptosis after exposure of 48 h.

Address correspondence to: Dr. Shuangqing Peng, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, People's Republic of China. E-mail: pengsq{at}hotmail.com