Chronic inflammation of the knee joint can induce chondrocyte death, leading to osteoarthritis (OA). Ca2+ influx through Ca2+ channels expressed in the chondrocyte plays a key role in promoting the inflammation and chondrocyte death. Voltage-gated K+ (Kv) channel can modulate this Ca2+ influx by regulating the resting membrane potential (RMP) in chondrocytes. Although it has been reported that an increase in intracellular Ca2+ concentration (Ca2+i) is associated with OA progression, the molecular mechanism(s) remain unclear. Therefore, the main goal of this study was to identify the mechanisms responsible for increases in Ca2+i in chondrocytes as a basis for understanding its role in OA progression. Our results reveal that in mouse chondrocytes treated with IL-1β, the expression of Kv1.6 channels was downregulated, and this resulted in a significant depolarization of the RMP. This downregulation of Kv1.6 channel in chondrocytes was also detected in OA model mice and in patients diagnosed with progressive OA. Furthermore, IL-1β treatment increased the expression of voltage-gated Cav1.2 channels. IL-1β-treated chondrocytes consistently showed an increase in resting Ca2+i, reduction or loss of mitochondrial membrane potential, and facilitation of apoptosis. These pathological changes were suppressed by recovery of Kv1.6 channel expression, or by treatment with nifedipine, a Cav1.2 channel inhibitor. In conclusion, IL-1β-induced downregulation of Kv1.6 channels leads to (i) depolarization of the RMP, (ii) an enhancement of Ca2+ influx through Cav1.2 channels, and (iii) an increase in Ca2+i which induces mitochondrial dysfunction and apoptosis in chondrocytes. Accordingly, Kv1.6 and Cav1.2 channels may be therapeutic targets for OA.
Kurata et al. (Mon,) studied this question.
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