软骨退变是骨性关节炎（OA）发病过程中的关键环节，其机制复杂。酪蛋白激酶1ε（CK1ε）是一种丝/苏氨酸蛋白激酶，也是Wnt通路的重要参与者。我们前期研究发现CK1ε在OA临床软骨标本中高表达，细胞实验发现其在IL-1β诱导软骨退变中的活性升高，而其抑制剂则明显抑制基质金属蛋白酶（MMP）的表达，缓解软骨退变。机制方面，我们发现P-120 catenin（CK1ε作用底物之一）在软骨退变中的磷酸化水平升高，伴JNK信号上调。因此，我们提出假说：CK1ε通过磷酸化P-120 catenin，激活Wnt/JNK通路，促进软骨细胞表达MMP而导致软骨退变，引起OA发病。本研究拟利用体外软骨细胞、关节软骨退变临床标本、OA小鼠动物模型以及CK1ε基因敲除动物等工具，阐明CK1ε在软骨退变中的作用及机制。本项目将从CK1ε这个新视点揭示软骨退变的发生机制，为OA的防治提供新的药物靶点和新思路。

Cartilage degeneration is a key step in the pathogenesis of osteoarthritis (OA), and its mechanism is complex. Casein kinase 1ε (CK1ε) is a serine/threonine protein kinase and also an important participant of the Wnt signal pathway. Our previous study found that CK1ε was highly expressed in OA cartilage specimens, and its activity was elevated in IL-1β-induced cartilage degeneration, while its inhibitors significantly inhibited matrix metalloproteinase (MMP) expression and alleviated cartilage degeneration. In terms of mechanism, we found that P-120 catenin (one of the substrates of CK1ε) increased phosphorylation in cartilage degeneration with up-regulation of JNK signal pathway. Therefore, we hypothesized that CK1ε activates the Wnt/JNK pathway by phosphorylating P-120 catenin, promoting the expression of MMP in chondrocytes, leading to cartilage degeneration and causing OA. This study intends to use the in vitro chondrocytes, articular cartilage degenerative specimens, OA mouse animal models and CK1ε knockout animals to clarify the role and mechanism of CK1ε in cartilage degeneration. This project will reveal the mechanism of cartilage degeneration from the new viewpoint of CK1ε, and provide new drug targets and new ideas for the prevention and treatment of OA.