1. Academic Validation
  2. EGR1 promotes the cartilage degeneration and hypertrophy by activating the Krüppel-like factor 5 and β-catenin signaling

EGR1 promotes the cartilage degeneration and hypertrophy by activating the Krüppel-like factor 5 and β-catenin signaling

  • Biochim Biophys Acta Mol Basis Dis. 2019 Sep 1;1865(9):2490-2503. doi: 10.1016/j.bbadis.2019.06.010.
Xuewu Sun 1 Hai Huang 1 Xin Pan 1 Shuoda Li 2 Ziang Xie 1 Yan Ma 1 Bin Hu 3 Jiying Wang 4 Zhijun Chen 1 Peihua Shi 5
Affiliations

Affiliations

  • 1 Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, China; Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, China.
  • 2 Department of Chinese medicine orthopedics, Ningbo Chinese Medicine Hospital, Ningbo, China.
  • 3 Department of Orthopedic Surgery, Second Affiliated Hospital, Zhejiang University, Hangzhou, China.
  • 4 Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, China.
  • 5 Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, China; Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, China. Electronic address: peihua_shi@zju.edu.cn.
Abstract

Osteoarthritis is one of the most common orthopedic diseases in elderly people who have lost their mobility. In this study,we observed abnormally high EGR1 expression in the articular cartilage of patients with osteoarthritis. We also found significantly high EGR1 expression in the articular cartilage of mice with destabilized medial meniscus (DMM)-induced osteoarthritis and 20-month-old mice. In vitro experiments indicated that IL-1β could significantly enhance EGR1 expression in primary mouse chondrocytes. EGR1 over-expression in chondrocytes using adenovirus could inhibit COl2A1 expression and enhance MMP9 and MMP13 expression. And silencing EGR1, using RNAi, had the opposite effects. Moreover, EGR1 over-expression accelerated chondrocyte hypertrophy in vitro, and EGR1 knockdown reversed this effect. We then explored the underlying mechanism. EGR1 over-expression increased Kruppel-Like Factor 5 (KLF5) protein level without influencing its synthesis. Enhanced EGR1 expression induced its integration with KLF5, leading to suppressed ubiquitination of KLF5. Moreover, EGR1 prompted β-catenin nuclear transportation to control chondrocyte hypertrophy. Ectopic expression of EGR1 in articular cartilage aggravated the degradation of the cartilage matrix in vivo. The EGR1 inhibitor, ML264, protected chondrocytes from IL-1β-mediated cartilage matrix degradation in vitro and DMM-induced osteoarthritis in vivo. Above all, we demonstrate the effect and mechanisms of EGR1 on osteoarthritis and provide evidence that the ML264 might be a potential drug for treating osteoarthritis in the future.

Keywords

Chondrocyte; EGR1; KLF5; Osteoarthritis.

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