Involvement of oxidative stress‐induced annulus fibrosus cell and nucleus pulposus cell ferroptosis in intervertebral disc degeneration pathogenesis

• Published in: Journal of cellular physiology Vol. 236; no. 4; pp. 2725 - 2739
• Main Authors: Yang, Run‐Ze, Xu, Wen‐Ning, Zheng, Huo‐Liang, Zheng, Xin‐Feng, Li, Bo, Jiang, Lei‐Sheng, Jiang, Sheng‐Dan
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-04-2021; John Wiley and Sons Inc
• Subjects: Animals; Annuli; Annulus Fibrosus - drug effects; Annulus Fibrosus - metabolism; Annulus Fibrosus - ultrastructure; Apoptosis; Autophagy; Butyl hydroperoxide; Carbolines - toxicity; Case-Control Studies; Cell death; Cells, Cultured; Deferoxamine; Deferoxamine - pharmacology; Degeneration; Degenerative disc disease; Disease Models, Animal; Ferritin; Ferroptosis; Ferroptosis - drug effects; Humans; intervertebral disc degeneration; Intervertebral Disc Degeneration - genetics; Intervertebral Disc Degeneration - metabolism; Intervertebral Disc Degeneration - pathology; Intervertebral Disc Degeneration - prevention & control; Intervertebral discs; Iron; Iron deficiency; Lipid Peroxidation; Lipids; Male; NCOA4; Nuclear Receptor Coactivators - genetics; Nuclear Receptor Coactivators - metabolism; Nuclei (cytology); Nucleus pulposus; Nucleus Pulposus - drug effects; Nucleus Pulposus - metabolism; Nucleus Pulposus - ultrastructure; Nutrient deficiency; Original; Original s; Oxidative stress; Oxidative Stress - drug effects; Pathogenesis; Peroxidation; Phagocytosis; Rats; Rats, Sprague-Dawley; Siderophores - pharmacology; Signal Transduction; Staining; tert-Butylhydroperoxide - toxicity; intervertebral disc degeneration; Ferroptosis; oxidative stress; NCOA4
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.30039

Ferroptosis is a necrotic form of regulated cell death that was associated with lipid peroxidation and free iron‐mediated Fenton reactions. It has been reported that iron deficiency had been implicated in the pathogenesis of intervertebral disc degeneration (IVDD) by activating apoptosis. However, the role of ferroptosis in the process of IVDD has not been illuminated. Here, we demonstrate the involvement of ferroptosis in IVDD pathogenesis. Our in vitro models show the changes in protein levels of ferroptosis marker and enhanced lipid peroxidation level during oxidative stress. Safranin O staining, hematoxylin‐eosin staining, and immunohistochemical were used to assess the IVDD after 8 weeks of surgical procedure in vivo. Treatment with ferrostatin‐1, deferoxamine, and RSL3 demonstrate the role of ferroptosis in tert‐butyl hydroperoxide (TBHP)‐treated annulus fibrosus cells (AFCs) and nucleus pulposus cells (NPCs). Ferritinophagy, nuclear receptor coactivator 4 (NCOA4)‐mediated ferritin selective autophagy, is originated during the process of ferroptosis in response to TBHP treatment. Knockdown and overexpression NCOA4 further prove TBHP may induce ferroptosis of AFCs and NPCs in an autophagy‐dependent way. These findings support a role for oxidative stress‐induced ferroptosis in the pathogenesis of IVDD.
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Ferroptosis is a necrotic form of regulated cell death that was associated with lipid peroxidation and free iron‐mediated Fenton reactions. It has been reported that iron deficiency had been implicated in the pathogenesis of intervertebral disc degeneration (IVDD) by activating apoptosis. However, the role of ferroptosis in the process of IVDD has not been illuminated. Here, we demonstrate the involvement of ferroptosis in IVDD pathogenesis.