Casein kinase 1 epsilon facilitates cartilage destruction in osteoarthritis through JNK pathway.

Osteoarthritis (OA) is a high-morbidity skeletal disease worldwide and the exact mechanisms underlying OA pathogenesis are not fully understood. Casein kinase 1 epsilon (CK1 epsilon) is a serine/threonine protein kinase, but its relationship with OA is still unknown. We demonstrated that CK1 epsilon was upregulated in articular cartilage of human patients with OA and mice with experimentally induced OA. Activity of CK1 epsilon, demonstrated by analysis of phosphorylated substrates, was significantly elevated in interleukin (IL)-1 beta-induced OA-mimicking chondrocytes. CK1 epsilon inhibitor or CK1 epsilon short hairpin RNA (shRNA) partially blocked matrix metalloproteinase (MMP) expression by primary chondrocytes induced by IL-1 beta, and also inhibited cartilage destruction in knee joints of experimental OA model mice. Conversely, overexpression of CK1 epsilon promoted chondrocyte catabolism. Previous studies indicated that CK1 epsilon was involved in canonical Wnt/beta-catenin signaling and noncanonical Wnt/c-Jun N-terminal kinase (JNK) signaling pathway. Interestingly, the activity of JNK but not beta-catenin decreased after CK1 epsilon knockdown in IL-1 beta-treated chondrocytes in vitro, and JNK inhibition reduced MMP expression in chondrocytes overexpressing CK1 epsilon, which illustrated that CK1 epsilon-mediated OA was based on JNK pathway. In conclusion, our results demonstrate that CK1 epsilon promotes OA development, and inhibition of CK1 epsilon could be a potential strategy for OA treatment in the future.