Activation of Nrf2 signaling by 4-octyl itaconate attenuates the cartilaginous endplate degeneration by inhibiting E3 ubiquitin ligase ZNF598. Issue 2 (February 2023)

• Record Type: Journal Article
• Authors: Huang, B.; Wu, H.; Zheng, L.; Wei, X.; Zheng, Z.; Wu, H.; Chen, J.; Shan, Z.; Liu, J.; Zhao, F.
• Is Part Of: Osteoarthritis and cartilage. Volume 31:Issue 2(2023)
• Page Start: 213
• Page End: 227
• Publication Date: 2023-02
• Subjects: Intervertebral disc degeneration -- Nrf2 -- 4-Octyl itaconate -- Cartilaginous endplate -- Inflammation; LBP low back pain -- CEP cartilaginous endplate -- NP nucleus pulposus -- IVDD Intervertebral disc degeneration -- MMP matrix metalloprotease -- ECM extracellular matrix -- NFE2L2 nuclear factor E2-related factor 2 -- 4OI 4-octyl itaconate -- MitoSOX mitochondrial superoxide -- IL-1β interleukin 1β -- TNF-α tumor necrosis factor α; Osteoarthritis -- Periodicals; Cartilage -- Periodicals; Osteoarthritis -- Periodicals; Cartilage -- Periodicals; Arthrose -- Périodiques; Articulations -- Maladies -- Périodiques; 616.7223005
• DOI: 10.1016/j.joca.2022.10.008
• Languages: English
• ISSNs: 1063-4584

Abstract

Summary: Objective: Cartilaginous endplate (CEP) degeneration is the main early manifestations of intervertebral disc degeneration (IVDD), and is closely related to the oxidative stress. Nrf2 (nuclear factor E2-related factor 2, NFE2L2) is a vital transcriptional factor of cellular antioxidant and anti-inflammatory responses. We aimed to illustrate whether the Nrf2 which was increased in expression by 4-octyl itaconate (4OI) could attenuate intervertebral disc degeneration through suppressing macrophage associated inflammation and catabolism of cartilaginous endplate. Methods: Firstly, we detected the expression of Nrf2 in human degenerative CEPs. Then, we performed in vitro, ex vivo and in vivo (a rat-tail puncture model) experiments to explore the role of 4OI in IVDD. Also, by cell co-culture experiments, we demonstrated 4OI restrained the macrophage-associated inflammatory responses. Finally, through western blotting and immunoprecipitation (IP) assay, we clarified the ZNF598-mediated ubiquitination of Nrf2. Results: We found decreased expression of Nrf2 in human degenerative CEPs. Using a rat IVDD model( n = 6), 4OI significantly ameliorated the progression of IVDD by MR images and histological analysis. Immunofluorescence results reveal that catabolism of CEPs and macrophage-associated inflammation are suppressed by 4OI treatment. Mechanistically, the 4OI increases Nrf2 expression and inhibits the secretion of inflammatory factors (IL-1β) by Lipopolysaccharide (LPS)-induced macrophages, thus preventing the inflammatory-related CEP degeneration. Meanwhile, 4OI suppresses the reactive oxygen species (ROS) production and catabolism of LPS-induced rat CEP cells. In addition, 4OI inhibits the ZNF598-dependent ubiquitination of Nrf2 in LPS-induced rat CEP cells. Conclusions: 4OI may alleviate IVDD by suppressing CEP degeneration and macrophage-associated inflammation. 4OI may be an alternative therapy for degenerative CEPs/IVDs.