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Eicosapentaenoic Acid-Induced Autophagy Attenuates Intervertebral Disc Degeneration by Suppressing Endoplasmic Reticulum Stress, Extracellular Matrix Degradation, and Apoptosis.

ABSTRACT: Intervertebral disc degeneration (IDD) is a major cause of low back pain (LBP), but there is still a lack of effective therapy. Multiple studies have reported that endoplasmic reticulum (ER) stress and extracellular matrix (ECM) degradation exert an enormous function on the occurrence and development of IDD. Autophagy can effectively repair ER stress and maintain ECM homeostasis. Eicosapentaenoic acid (EPA) can specifically induce autophagy. The purpose of this study is to demonstrate that EPA can promote autophagy, reduce ECM degradation and ER stress in vitro, thereby reducing cell apoptosis, and the protective effects of EPA in an IDD-rat model in vivo. Western blot and immunofluorescence were used to detect the autophagic flux, ER stress, ECM degradation, and apoptosis in nucleus pulposus cells (NPCs) treated by EPA. We also used puncture-induced IDD rats as experimental subjects to observe the therapeutic effect of EPA on IDD. Our findings indicated that EPA can effectively improve the autophagy activity in NPCs, inhibit the endoplasmic reticulum stress process, reduce the degree of cell apoptosis, and exert protective effects on the anabolism and catabolism of ECM. In addition, in vivo investigations demonstrated that EPA ameliorated the progression of puncture-induced IDD in rats. In conclusion, this study revealed the intrinsic mechanisms of EPA's protective role in NPCs and its potential therapeutic significance for the treatment of IDD.

SUBMITTER: Lin Z

PROVIDER: S-EPMC8599281 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background contextNonphysiological mechanical loading and inflammation are both critically involved in intervertebral disc (IVD) degeneration, which is characterized by an increase in cytokines and matrix metalloproteases (MMPs) in the nucleus pulposus (NP). This process is known to be mediated by the NF-κB pathway.Clinical significanceCurrent clinical treatments for IVD degeneration focus on the alleviation of symptoms rather than targeting the underlying mechanism. Injection of an NF-κB inhibitor may attenuate the progression of IVD degeneration.PurposeTo investigate the ability of the NF-κB inhibitor, NEMO binding domain peptide (NBD), to alter IVD degeneration processes by reducing IL-1β- and mechanically-induced cytokine and MMP levels in human nucleus pulposus cells in vitro, and by attenuating IVD degeneration in an in vivo rat model for disc degeneration.Study designExperimental in vitro and animal model.Patient sampleDiscarded specimens of lumbar disc from 21 patients, and 12 Sprague Dawley rats.Outcome measuresGene and protein expression, cell viability, µMRI and histology.MethodsIL-1β-prestimulated human nucleus pulposus cells embedded into fibrin constructs were loaded in the Flexcell FX-5000 compression system at 5 kPa and 1 Hz for 48 hours in the presence and absence of NBD. Unloaded hNPC/fibrin constructs served as controls. Cell viability in loaded and unloaded constructs was quantified, and gene and protein expression levels determined. For in vivo testing, a rat needle disc puncture model was employed. Experimental groups included injured discs with and without NBD injection and uninjured controls. Levels of disc degeneration were determined via µMRI, qPCR and histology. Funding sources include $48,874 NASS Young Investigator Research Grant and $119,174 NIH 5K01AR071512-02. There were no applicable financial relationships or conflicts of interest.ResultsMechanical compression of hNPC/fibrin constructs resulted in upregulation of MMP-3 and IL-8. Supplementation of media with 10 μM NBD during loading increased cell viability, and decreased MMP-3 gene and protein levels. IVD injury in rat resulted in an increase in MMP-3, IL-1β and IL-6 gene expression. Injections of 250 µg of NBD during disc injury resulted in decreased IL-6 gene expression. µMRI analysis demonstrated a reduction of disc hydration in response to disc needle injury, which was attenuated in NBD-treated IVDs. Histological evaluation showed NP and AF lesion in injured discs, which was attenuated by NBD injection.ConclusionsThe results of this study show NBD peptide's capacity to reduce IL-1β- and loading-induced MMP-3 levels in hNPC/fibrin constructs while increasing the cells' viability, and to attenuate IVD degeneration in rat, involving downregulation of IL-6. Therefore, NBD may be a potential therapeutic agent to treat IVD degeneration.

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Eicosapentaenoic Acid-Induced Autophagy Attenuates Intervertebral Disc Degeneration by Suppressing Endoplasmic Reticulum Stress, Extracellular Matrix Degradation, and Apoptosis.

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