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.
Highlights
Osteoarthritis (OA) is a progressive degenerative disease of the cartilage that leads to irreversible cartilage loss, joint pain and dysfunction
Evidence is accumulating that an increased incidence of chondrocyte apoptosis during aging is responsible for hypocellularity associated with degradation and/or pathological remodeling of the cartilage matrix, and exacerbates the risk of degenerative joint diseases such as OA [2,3,4]
Our results show that etodolac effectively reverses TNFα-induced elicitation of ICl,vol and inhibits apoptotic cell volume decrease (AVD) and elevation of caspase activity
Summary
Osteoarthritis (OA) is a progressive degenerative disease of the cartilage that leads to irreversible cartilage loss, joint pain and dysfunction. Chondrocyte apoptosis is a functionally important phenomenon in the development and growth of articular cartilage under physiological conditions. Evidence is accumulating that an increased incidence of chondrocyte apoptosis during aging is responsible for hypocellularity associated with degradation and/or pathological remodeling of the cartilage matrix, and exacerbates the risk of degenerative joint diseases such as OA [2,3,4]. It is suggested that aberrant activation of ICl,vol under isosmotic condition contributes to the cell shrinkage associated with induction of apoptosis (referred to as apoptotic volume decrease, AVD) in various cell types including chondrocytes [9]. Accumulating evidence suggests that COX-2 regulates cell growth and proliferation as well as cell death in various tumors [20,21,22] It is still poorly understood whether COX-2 blocker affects chondrocyte apoptosis. Our results show that etodolac effectively reverses TNFα-induced elicitation of ICl,vol and inhibits AVD and elevation of caspase activity
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