変形性膝関節症の軟骨細胞におけるKv1.6チャネルの役割

抄録

Osteoarthritis (OA) is a chronic inflammatory disease characterized by a decrease in cartilage matrix, disorders of joint movement, and severe pain. Previous studies have suggested that an increase in intracellular Ca²⁺ concentration ([Ca²⁺]­_i) in chondrocytes is associated with OA progression. However, the mechanism underlying this increased [Ca²⁺]_i  is unknown. In the present study, we aimed to elucidate this mechanism and its roles in OA progression. Primary chondrocytes were isolated from C57BL/6 mice, and treated with interleukin (IL)-1β, a major cytokine secreted into synovial fluid during OA. In IL-1β-treated chondrocytes, resting membrane potential was depolarized, and resting [Ca²⁺]_i was increased due to the downregulation of voltage-gated K⁺ channel, Kv1.6. This downregulation of Kv1.6 was also detected in chondrocytes from OA model mice and OA patients. IL-1β induced depolarization of mitochondrial membrane potential (ΔΨm) and cell death. In contrast, overexpression of Kv1.6 in chondrocytes using adenovirus reduced resting [Ca²⁺]­_i, increased ΔΨm, and inhibited cell death. In summary, IL-1β downregulates Kv1.6 and increases resting [Ca²⁺]­_i, resulting in mitochondrial Ca²⁺ overload and subsequent cell death. Our findings may contribute to the understanding of OA pathogenesis and the development of new treatments for OA.