1. Academic Validation
  2. Knockdown of SGK1 alleviates the IL-1β-induced chondrocyte anabolic and catabolic imbalance by activating FoxO1-mediated autophagy in human chondrocytes

Knockdown of SGK1 alleviates the IL-1β-induced chondrocyte anabolic and catabolic imbalance by activating FoxO1-mediated autophagy in human chondrocytes

  • FEBS J. 2020 Jan;287(1):94-107. doi: 10.1111/febs.15009.
Wei Huang 1 2 Chao Cheng 1 Wen-Shan Shan 1 Zhen-Fei Ding 1 Fu-En Liu 1 Wei Lu 1 Wei He 3 Jie-Gou Xu 3 Zong-Sheng Yin 1
Affiliations

Affiliations

  • 1 Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 2 Department of Orthopaedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 3 School of Basic Medical Sciences, Anhui Medical University, Hefei, China.
Abstract

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.

Keywords

FoxO1; SGK1; autophagy; chondrocyte; osteoarthritis.

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    Target
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  • HY-100596
    99.83%, Foxo1 Inhibitor