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The COX-2 Selective Blocker Etodolac Inhibits TNFα-Induced Apoptosis in Isolated Rabbit Articular Chondrocytes
Department of Orthopaedic Surgery, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
Department of Physiology, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
* Author to whom correspondence should be addressed.
Received: 31 July 2013; in revised form: 6 September 2013 / Accepted: 10 September 2013 / Published: 30 September 2013
Abstract: Chondrocyte apoptosis contributes to the disruption of cartilage integrity in osteoarthritis (OA). Recently, we reported that activation of volume-sensitive Cl− current (ICl,vol) mediates cell shrinkage, triggering apoptosis in rabbit articular chondrocytes. A cyclooxygenase (COX) blocker is frequently used for the treatment of OA. In the present study, we examined in vitro effects of selective blockers of COX on the TNFα-induced activation of ICl,vol in rabbit chondrocytes using the patch-clamp technique. Exposure of isolated chondrocytes to TNFα resulted in an obvious increase in membrane Cl− conductance. The TNFα-evoked Cl− current exhibited electrophysiological and pharmacological properties similar to those of ICl,vol. Pretreatment of cells with selective COX-2 blocker etodolac markedly inhibited ICl,vol activation by TNFα as well as subsequent apoptotic events such as apoptotic cell volume decrease (AVD) and elevation of caspase-3/7 activity. In contrast, a COX-1 blocker had no effect on the decrease in cell volume or the increase in caspase-3/7 activity induced by TNFα. Thus, the COX-2-selective blocker had an inhibitory effect on TNFα-induced apoptotic events, which suggests that this drug would have efficacy for the treatment of OA.
Keywords: chondrocyte; apoptosis; TNFα; COX-2; osteoarthritis
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Kumagai, K.; Kubo, M.; Imai, S.; Toyoda, F.; Maeda, T.; Okumura, N.; Matsuura, H.; Matsusue, Y. The COX-2 Selective Blocker Etodolac Inhibits TNFα-Induced Apoptosis in Isolated Rabbit Articular Chondrocytes. Int. J. Mol. Sci. 2013, 14, 19705-19715.
Kumagai K, Kubo M, Imai S, Toyoda F, Maeda T, Okumura N, Matsuura H, Matsusue Y. The COX-2 Selective Blocker Etodolac Inhibits TNFα-Induced Apoptosis in Isolated Rabbit Articular Chondrocytes. International Journal of Molecular Sciences. 2013; 14(10):19705-19715.
Kumagai, Kousuke; Kubo, Mitsuhiko; Imai, Shinji; Toyoda, Futoshi; Maeda, Tsutomu; Okumura, Noriaki; Matsuura, Hiroshi; Matsusue, Yoshitaka. 2013. "The COX-2 Selective Blocker Etodolac Inhibits TNFα-Induced Apoptosis in Isolated Rabbit Articular Chondrocytes." Int. J. Mol. Sci. 14, no. 10: 19705-19715.