Interleukin-1β downregulates K+ currents through Kv1.6 channels and promotes apoptosis by enhancing Ca2+ influx in chondrocytes.

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) channels 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 channels 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 1) depolarization of the RMP, 2) an enhancement of Ca2+ influx through Cav1.2 channels, and 3) 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.NEW & NOTEWORTHY Our results reveal that Kv1.6 channels in mouse chondrocytes contribute to cell survival by regulating the resting membrane potential (RMP) and thus modulating intracellular Ca2+ concentration ([Ca2+]i). Specifically, IL-1β can downregulate Kv1.6 channels and result in RMP depolarization, which increases Ca2+ influx through Cav1.2 channels and promotes mitochondrial dysfunction and apoptosis. Downregulation of Kv1.6 channels was detected in chondrocytes of osteoarthritis (OA) model mice and OA patients. These findings suggest that Kv1.6 and/or Cav1.2 channels may be potential therapeutic targets for OA.