Casein kinase 1 epsilon facilitates cartilage destruction in osteoarthritis through JNK pathway
Casein kinase 1 epsilon facilitates cartilage destruction in osteoarthritis through JNK pathway
复制标题
酪蛋白激酶 1 epsilon 通过 JNK 途径促进骨关节炎中的软骨破坏
DOI：
10.1096/fj.201902672r
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发表时间：
2020-05-01
期刊：
影响因子：
4.8
通讯作者：
Rong Limin
中科院分区：
文献类型：
--
作者：
He Tianwei;Wu Depeng;Rong Limin
骨关节炎（OA）是一种世界范围内发病率较高的骨骼疾病，其发病机制尚未完全阐明。酪蛋白激酶1 α（CK 1 β）是一种丝氨酸/苏氨酸蛋白激酶，但其与OA的关系尚不清楚。我们证明，CK 1 β在人类OA患者和实验诱导的OA小鼠的关节软骨中上调。通过磷酸化底物分析证实，在白细胞介素（IL）-1 β诱导的OA模拟软骨细胞中，CK 1 β的活性显著升高。CK 1 β抑制剂或CK 1 β短发夹RNA（shRNA）可部分阻断IL-1 β诱导的原代软骨细胞表达基质金属蛋白酶（MMP），并抑制实验性OA模型小鼠膝关节软骨的破坏。相反，CK 1 β过表达促进软骨细胞增殖。研究表明，CK 1 β参与经典Wnt/beta-catenin信号通路和非经典Wnt/c-Jun N-末端激酶（JNK）信号通路。有趣的是，在IL-1 β处理的体外软骨细胞中，CK 1 ε敲低后JNK而不是β-catenin的活性降低，并且JNK抑制降低了过表达CK 1 ε的软骨细胞中MMP的表达，这说明CK 1 ε介导的OA是基于JNK通路。总之，我们的研究结果表明，CK 1 β促进OA的发展，和CK 1 β的抑制可能是一个潜在的策略，在未来的OA治疗。
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.