Molecular mechanisms of cell death in intervertebral disc degeneration (Review)

AbstractIntervertebral disc degeneration (IDD) is a common and early-onset pathogenesis in the human lifespan that can increase the risk of low back pain. More clarification of the molecular mechanisms associated with the onset and progression of IDD is likely to help establish novel preventive and therapeutic strategies. Recently, mitochondria have been increasingly recognized as participants in regulating glycolytic metabolism, which has historically been regarded as the main metabolic pathway in intervertebral discs due to their avascular properties. Indeed, mitochondrial structural and functional disruption has been observed in degenerated nucleus pulposus (NP) cells and intervertebral discs. Multilevel and well-orchestrated strategies, namely, mitochondrial quality control (MQC), are involved in the maintenance of mitochondrial integrity, mitochondrial proteostasis, the mitochondrial antioxidant system, mitochondrial dynamics, mitophagy, and mitochondrial biogenesis. Here, we address the key evidence and current knowledge of the role of mitochondrial function in the IDD process and consider how MQC strategies contribute to the protective and detrimental properties of mitochondria in NP cell function. The relevant potential therapeutic treatments targeting MQC for IDD intervention are also summarized. Further clarification of the functional and synergistic mechanisms among MQC mechanisms may provide useful clues for use in developing novel IDD treatments.

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The Use of Stem Cells in the Treatment of Intervertebral Disc Degeneration

Annals of the Russian academy of medical sciences ◽

10.15690/vramn729 ◽

2016 ◽

Vol 71 (5) ◽

pp. 359-366

Author(s):

V. A. Byvaltsev ◽

I. A. Stepanov ◽

L. A. Bardonova ◽

E. G. Belykh

Keyword(s):

Stem Cells ◽

Intervertebral Disc ◽

Disc Degeneration ◽

Intervertebral Disc Degeneration ◽

Molecular Mechanisms ◽

Experimental Studies ◽

Spinal Pain ◽

Underlying Disease ◽

Current Data ◽

Bone Marrow Tissue

The paper presents a review of current data on the use of stem cells in the treatment of intervertebral disc degeneration. Acute spinal pain is often a consequence of the pathology affecting the intervertebral disc. Many applied therapeutic techniques do not provide effective results as expected because most of them address symptoms, but do not treat the underlying disease. We have outlined current findings on the molecular mechanisms of intervertebral disc degeneration, analyzed international experimental studies demonstrating the feasibility of a stem cell therapy for intervertebral disc degeneration. The conducted studies reported on the clinical application of mesenchymal stem cells or stem cells derived from adipose, synovium, and bone marrow tissue. The most pressing and undetermined issues that require further experimental and clinical studies are indicated and defined in the article.

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Carbohydrate sulfotransferase 3 (CHST3) overexpression promotes cartilage endplate‐derived stem cells (CESCs) to regulate molecular mechanisms related to repair of intervertebral disc degeneration by rat nucleus pulposus

Journal of Cellular and Molecular Medicine ◽

10.1111/jcmm.16440 ◽

2021 ◽

Author(s):

Yunzhi Guan ◽

Chi Sun ◽

Fei Zou ◽

Hongli Wang ◽

Feizhou Lu ◽

...

Keyword(s):

Stem Cells ◽

Intervertebral Disc ◽

Nucleus Pulposus ◽

Disc Degeneration ◽

Intervertebral Disc Degeneration ◽

Molecular Mechanisms ◽

Cartilage Endplate

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Cell Senescence: A Nonnegligible Cell State under Survival Stress in Pathology of Intervertebral Disc Degeneration

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/9503562 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Yuang Zhang ◽

Biao Yang ◽

Jingkai Wang ◽

Feng Cheng ◽

Kesi Shi ◽

...

Keyword(s):

Risk Factors ◽

Cell Death ◽

Intervertebral Disc ◽

Disc Degeneration ◽

Intervertebral Disc Degeneration ◽

Cellular Level ◽

Cell Senescence ◽

Extrinsic Factors ◽

Cell State ◽

Potential Risk Factors

The intervertebral disc degeneration (IDD) with increasing aging mainly manifests as low back pain (LBP) accompanied with a loss of physical ability. These pathological processes can be preliminarily interpreted as a series of changes at cellular level. In addition to cell death, disc cells enter into the stagnation with dysfunction and deteriorate tissue microenvironment in degenerative discs, which is recognized as cell senescence. During aging, many intrinsic and extrinsic factors have been proved to have strong connections with these cellular senescence phenomena. Growing evidences of these connections require us to gather up critical cues from potential risk factors to pathogenesis and relative interventions for retarding cell senescence and attenuating degenerative changes. In this paper, we try to clarify another important cell state apart from cell death in IDD and discuss senescence-associated changes in cells and extracellular microenvironment. Then, we emphasize the role of oxidative stress and epigenomic perturbations in linking risk factors to cell senescence in the onset of IDD. Further, we summarize the current interventions targeting senescent cells that may exert the benefits of antidegeneration in IDD.

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miR-142-3p and HMGB1 Are Negatively Regulated in Proliferation, Apoptosis, Migration and Autophagy of Cartilage Endplate Cells

10.21203/rs.3.rs-272616/v1 ◽

2021 ◽

Author(s):

Bo Wang ◽

Demin Ji ◽

Wenhua Xing ◽

Feng Li ◽

Zhi Huang ◽

...

Keyword(s):

Intervertebral Disc ◽

Disc Degeneration ◽

Intervertebral Disc Degeneration ◽

Target Gene ◽

Molecular Mechanisms ◽

Target Genes ◽

Vital Role ◽

Luciferase Assay ◽

Expression Levels ◽

Cartilage Endplate

Abstract Background: cartilage endplate (CEP) degeneration plays a vital role in the pathological process of intervertebral disc degeneration. It has been previously reported that microRNAs may participate in the occurrence and development of intervertebral disc degeneration through regulating its’ target genes directly. The regulatory roles of miR-142-3p /HMGB1 in some orthopedic diseases have been determined successively, but there was no report about the degeneration of CEP. Therefore, we aimed to determine the regulation of miR-142-3p /HMGB1or potential molecular mechanisms on proliferation, apoptosis, migration, and autophagy of CEP cells.Methods: the target gene of miR-142-3p was determined by double luciferase assay. We selected ATDC5 cell lines. CCK-8 method was used to detect cell proliferation. Real-time fluorescence quantitative PCR was used to determine gene expression levels, and western blot analysis was used to determine protein expression levels. We chose the flow cytometry to measure cell apoptosis and cell cycle.Results: the result of luciferase detection showed that the target gene of miR-142-3p in CEP cells was HMGB1. Knockdown the miR-142-3p inhibited the expression level of HMGB1, the proliferation and migration of CEP cells, but it promoted apoptosis of CEP cells. In addition, the detection results of the proteins related to apoptosis or autophagy showed that knockdown of miR-142-3p promoted apoptosis and autophagy.Conclusion: The negative regulation of miR-142-3p /HMGB1 can affect the proliferation, apoptosis, migration, and autophagy of CEP cells. Our results provided a new idea for the targeted treatment of CEP degeneration by inhibiting the expression of HMGB1.

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Autophagic Degradation of Gasdermin D Protects against Nucleus Pulposus Cell Pyroptosis and Retards Intervertebral Disc Degeneration In Vivo

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/5584447 ◽

2021 ◽

Vol 2021 ◽

pp. 1-22

Author(s):

Zhiwei Liao ◽

Suyun Li ◽

Rong Liu ◽

Xiaobo Feng ◽

Yunsong Shi ◽

...

Keyword(s):

Cell Death ◽

Intervertebral Disc ◽

Nucleus Pulposus ◽

Disc Degeneration ◽

Intervertebral Disc Degeneration ◽

Degradation Mechanism ◽

Nucleus Pulposus Cell ◽

Social Burden ◽

Related Proteins

Intervertebral disc degeneration (IDD) is the primary culprit of low back pain and renders heavy social burden worldwide. Pyroptosis is a newly discovered form of programmed cell death, which is also involved in nucleus pulposus (NP) cells during IDD progression. Moderate autophagy activity is critical for NP cell survival, but its relationship with pyroptosis remains unknown. This study is aimed at investigating the relationship between autophagy and pyroptotic cell death. The pyroptosis executor N-terminal domain of gasdermin D (GSDMD-N) and inflammation-related proteins were measured in lipopolysaccharide- (LPS-) treated human NP cells. Inhibition of autophagy by siRNA transfection and chemical drugs aggravated human NP cell pyroptosis. Importantly, we found that the autophagy-lysosome pathway and not the proteasome pathway mediated the degradation of GSDMD-N as lysosome dysfunction promoted the accumulation of cytoplasmic GSDMD-N. Besides, P62/SQSTM1 colocalized with GSDMD-N and mediated its degradation. The administration of the caspase-1 inhibitor VX-765 could reduce cell pyroptosis as confirmed in a rat disc IDD model in vivo, whereas ATG5 knockdown significantly accelerated the progression of IDD. In conclusion, our study indicated that autophagy protects against LPS-induced human NP cell pyroptosis via a P62/SQSTM1-mediated degradation mechanism and the inhibition of pyroptosis retards IDD progression in vivo. These findings deepen the understanding of IDD pathogenesis and hold implications in unraveling therapeutic targets for IDD treatment.

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