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.
Keywords
Abbreviations:
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)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: October 17, 2022
Accepted:
October 11,
2022
Received:
May 17,
2022
Identification
Copyright
© 2022 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
