Molecular Mechanisms of Intervertebral Disc Degeneration

Rider, Sean M; Mizuno, Shuichi; Kang, James D.

doi:10.22603/ssrr.2017-0095

Cited by 56 publications

(42 citation statements)

References 174 publications

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“…Jiang et al investigated autophagy and apoptosis as well as their interactions in NPCs under OS [ 9 ]. Other studies have determined that the expression of collagen type II and aggrecan was downregulated in hydroperoxide-induced NPCs [ 41 ]. However, these do not fully explain the decrease in NPCs and ECM degradation, as seen by the failure of drugs targeting these mechanisms to fully treat IVDD.…”

Section: Discussionmentioning

confidence: 99%

Ferroportin-Dependent Iron Homeostasis Protects against Oxidative Stress-Induced Nucleus Pulposus Cell Ferroptosis and Ameliorates Intervertebral Disc Degeneration In Vivo

Song

Luo

et al. 2021

Oxidative Medicine and Cellular Longevity

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Ferroptosis is a specialized form of regulated cell death that is charactered by iron-dependent lethal lipid peroxidation, a process associated with multiple diseases. However, its role in the pathogenesis of intervertebral disc degeneration (IVDD) is rarely investigated. This study is aimed at investigating the role of ferroptosis in oxidative stress- (OS-) induced nucleus pulposus cell (NPC) decline and the pathogenesis of IVDD and determine the underlying regulatory mechanisms. We used tert-butyl hydroperoxide (TBHP) to simulate OS conditions around human NPCs. Flow cytometry and transmission electron microscopy were used to identify ferroptosis, while iron assay kit, Perl’s staining, and western blotting were performed to assay the intracellular iron levels. A ferroportin- (FPN-) lentivirus and FPN-siRNA were constructed and used to explore the relationship between FPN, intracellular iron homeostasis, and ferroptosis. Furthermore, hinokitiol, a bioactive compound known to specifically resist OS and restore FPN function, was evaluated for its therapeutic role in IVDD both in vitro and in vivo. The results indicated that intercellular iron overload plays an essential role in TBHP-induced ferroptosis of human NPCs. Mechanistically, FPN dysregulation is responsible for intercellular iron overload under OS. The increase in nuclear translocation of metal-regulatory transcription factor 1 (MTF1) restored the function of FPN, abolished the intercellular iron overload, and protected cells against ferroptosis. Additionally, hinokitiol enhanced the nuclear translocation of MTF1 by suppressing the JNK pathway and ameliorated the progression of IVDD in vivo. Taken together, our results demonstrate that ferroptosis and FPN dysfunction are involved in the NPC depletion and the pathogenesis of IVDD under OS. To the best of our knowledge, this is the first study to demonstrate the protective role of FPN in ferroptosis of NPCs, suggesting its potential used as a novel therapeutic target against IVDD.

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Section: Discussionmentioning

confidence: 99%

Ferroportin-Dependent Iron Homeostasis Protects against Oxidative Stress-Induced Nucleus Pulposus Cell Ferroptosis and Ameliorates Intervertebral Disc Degeneration In Vivo

Song

Luo

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…Intervertebral disc degeneration (IDD) is one of the most common causes of lower back pain and related disability [ 1 , 2 ]. Back pain is a common chronic medical problem worldwide, such that over 80% of adults are estimated to have suffered from back pain at some point in their lives [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of HDAC4 by GSK3β leads to downregulation of KLF5 and ASK1 and prevents the progression of intravertebral disc degeneration

et al. 2021

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Background Intervertebral disc degeneration (IDD) is a major cause of lower back pain. This study aimed at exploring the effects of histone deacetylase 4 (HDAC4) and its upstream and downstream signaling molecules on IDD development. Methods A murine IDD model was established by inducing a needle puncture injury to the vertebrate, whereupon we isolated and transfected of nucleus pulposus (NP) cells. Disc height index (DHI) of the mice was determined by X-ray tomography, while the pain experienced by the IDD mice was evaluated by mechanical and thermal sensitivity tests. Next, the interaction between GSK3β and HDAC4 as well as that between HDAC4 and KLF5 acetylation was assessed by co-immunoprecipitation, while the promoter region binding was assessed identified by chromatin immunoprecipitation. By staining methods with TUNEL, Safranin O fast green, and hematoxylin and eosin, the NP cell apoptosis, degradation of extracellular matrix, and morphology of intervertebral disc tissues were measured. Furthermore, mRNA and protein expressions of GSK3β, HDAC4, KLF5, and ASK1, as well as the extent of HDAC4 phosphorylation, were determined by RT-qPCR and Western blotting. Results GSK3β was identified to be downregulated in the intervertebral disc tissues obtained from IDD mice, while HDAC4, KLF5, and ASK1 were upregulated. HDAC4 silencing alleviated IDD symptoms. It was also found that GSK3β promoted the phosphorylation of HDAC4 to increase its degradation, while HDAC4 promoted ASK1 expression through upregulating the expression of KLF5. In IDD mice, GSK3β overexpression resulted in increased DHI, inhibition of NP cell apoptosis, alleviation of disc degeneration, and promoted mechanical and thermal pain thresholds. However, HDAC4 overexpression reversed these effects by promoting ASK1 expression. Conclusion Based on the key findings of the current study, we conclude that GSK3β can promote degradation of HDAC4, which lead to an overall downregulation of the downstream KLF5/ASK1 axis, thereby alleviating the development of IDD.

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“…Indeed, we have recently reported a significant association between the circulating levels of growth and differentiation factor 15 (GDF-15) and LBP disability in a large community-based sample [ 6 ]. Taking into account proposed involvement of inflammation in intervertebral disc (IVD) degeneration [ 7 , 8 , 9 , 10 ], the search for peripheral biomarkers has been conducted among pro-inflammatory factors that revealed, however, the inconsistent results [ 11 , 12 ]. Although controversial, other studies have suggested obesity as a risk factor in the development of LBP and other MSP syndromes [ 13 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Circulating Levels of Visceral Adipose Tissue-Derived Serine Protease Inhibitor (Vaspin) Appear as a Marker of Musculoskeletal Pain Disability

et al. 2020

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Musculoskeletal pain (MSP), specifically low back pain (LBP), is often associated with several adipose tissue-derived cytokines (adipokines) and body composition, but their correlations with the LBP-related disability/severity phenotypes remain poorly understood. In this cross-sectional study, two self-reported validated questionnaires were used to collect back pain and disability data in an ethnically homogeneous family-based population sample (N = 1078). Plasma levels of relatively new adipokines, vaspin and adipsin, were detected by ELISA. Body composition parameters, including fat, skeletal muscle mass, extracellular water (ECW), and others were assessed through bioelectrical impedance analysis (BIA) technology. Statistical analysis was conducted, accounting for the familial composition of the sample. The multiple regression analyses with four LBP-related phenotypes as dependent variables consistently showed, for the first time, the significant associations with vaspin levels, regardless of other covariates. The odds ratios (OR)/SD ranged between 1.24 (95%CI = 1.03–1.50) and 1.33 (95%CI = 1.07–1.64), depending on the LBP phenotype. Among the tested body composition covariates, only ECW levels displayed consistent and highly significant associations with all tested LBP phenotypes (OR from 1.43, 95%CI = 1.14–1.79 to 1.68, 95%CI = 1.26–2.24). The results clearly suggest that circulating concentrations of vaspin and ECW levels could serve as biomarkers of MSP/LBP severity and complications.

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Molecular Mechanisms of Intervertebral Disc Degeneration

Cited by 56 publications

References 174 publications

Ferroportin-Dependent Iron Homeostasis Protects against Oxidative Stress-Induced Nucleus Pulposus Cell Ferroptosis and Ameliorates Intervertebral Disc Degeneration In Vivo

Ferroportin-Dependent Iron Homeostasis Protects against Oxidative Stress-Induced Nucleus Pulposus Cell Ferroptosis and Ameliorates Intervertebral Disc Degeneration In Vivo

Inhibition of HDAC4 by GSK3β leads to downregulation of KLF5 and ASK1 and prevents the progression of intravertebral disc degeneration

Circulating Levels of Visceral Adipose Tissue-Derived Serine Protease Inhibitor (Vaspin) Appear as a Marker of Musculoskeletal Pain Disability

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