Interleukin-1β downregulates K ⁺ currents through K _v 1.6 channels and promotes apoptosis by enhancing Ca ²⁺ 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⁺ (K_v) 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 K_v1.6 channels was downregulated, and this resulted in a significant depolarization of the RMP. This downregulation of K_v1.6 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 Ca_v1.2 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 K_v1.6 channel expression or by treatment with nifedipine, a Ca_v1.2 channel inhibitor. In conclusion, IL-1β-induced downregulation of K_v1.6 channels leads to <i>1</i>) depolarization of the RMP, <i>2</i>) an enhancement of Ca²⁺ influx through Ca_v1.2 channels, and <i>3</i>) an increase in [Ca²⁺]_i, which induces mitochondrial dysfunction and apoptosis in chondrocytes. Accordingly, K_v1.6 and Ca_v1.2 channels may be therapeutic targets for OA.<b>NEW & NOTEWORTHY</b> Our results reveal that K_v1.6 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 K_v1.6 channels and result in RMP depolarization, which increases Ca²⁺ influx through Ca_v1.2 channels and promotes mitochondrial dysfunction and apoptosis. Downregulation of K_v1.6 channels was detected in chondrocytes of osteoarthritis (OA) model mice and OA patients. These findings suggest that K_v1.6 and/or Ca_v1.2 channels may be potential therapeutic targets for OA.