Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
Department of Orthopaedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
FEBS J. 2020 Jan;287(1):94-107. doi: 10.1111/febs.15009. Epub 2019 Jul 31.
Osteoarthritis (OA) is a common joint disease characterized by the progressive degeneration of articular cartilage with no effective treatment methods available. Cartilage degeneration is closely related to an anabolic and catabolic imbalance in chondrocytes, and accumulating evidence has revealed that autophagy is a crucial protective mechanism that maintains the balance of anabolic and catabolic activities. Therefore, studies aiming to identify additional genes that regulate autophagy as a promising therapeutic strategy for OA are needed. In this study, we analyzed the GSE113825 datasets from Gene Expression Omnibus and validated that serum- and glucocorticoid-regulated kinase 1 (SGK1) was upregulated in OA cartilage. Based on the results from loss-of-function studies, SGK1 silencing promoted the deposition of glycosaminoglycans in interleukin 1 beta (IL-1β)-treated chondrocytes, and significantly alleviated IL-1β-induced downregulation of Collagen II and Aggrecan, as well as the upregulation of a disintegrin and metalloproteinase with thrombospondin motifs 5 and matrix metalloproteinase-13. Furthermore, SGK1 knockdown reversed the IL-1β-induced chondrocyte anabolic and catabolic imbalance by activating autophagy. Moreover, SGK1 directly bound to forkhead box protein O1 (FoxO1) and increased its phosphorylation, which in turn resulted in its translocation from the nucleus. The decreased FoxO1 levels led to a decrease in LC3-I/LC3-II conversion and Beclin-1 levels, subsequently inhibiting autophagosome formation and increasing P62 levels, thus indicating a downregulation of autophagy. Taken together, we identified a critical role of SGK1 in the IL-1β-induced chondrocyte anabolic and catabolic imbalance, which may represent a potential novel therapeutic target for OA.
骨关节炎（OA）是一种常见的关节疾病，其特征是关节软骨进行性退化，目前尚无有效的治疗方法。软骨退化与软骨细胞合成代谢和分解代谢失衡密切相关，越来越多的证据表明，自噬是维持合成代谢和分解代谢活动平衡的关键保护机制。因此，需要研究鉴定其他调节自噬的基因，作为 OA 的一种有前途的治疗策略。在本研究中，我们分析了来自基因表达综合数据库的 GSE113825 数据集，验证了 SGK1 在 OA 软骨中上调。基于功能丧失研究的结果，SGK1 沉默促进了白细胞介素 1β（IL-1β）处理的软骨细胞中糖胺聚糖的沉积，并显著缓解了 IL-1β 诱导的 Collagen II 和 Aggrecan 下调，以及 a disintegrin and metalloproteinase with thrombospondin motifs 5 和 matrix metalloproteinase-13 的上调。此外，SGK1 敲低通过激活自噬逆转了 IL-1β 诱导的软骨细胞合成代谢和分解代谢失衡。此外，SGK1 直接与叉头框蛋白 O1（FoxO1）结合并增加其磷酸化，从而导致其从核内易位。FoxO1 水平的降低导致 LC3-I/LC3-II 转化和 Beclin-1 水平降低，随后抑制自噬体形成并增加 P62 水平，从而表明自噬下调。总之，我们确定了 SGK1 在 IL-1β 诱导的软骨细胞合成代谢和分解代谢失衡中的关键作用，这可能代表 OA 的一个潜在新的治疗靶点。
