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Orthopaedic Surgery Jul 2022Intervertebral disc degeneration (IDD) causes a variety of signs and symptoms, such as low back pain (LBP), intervertebral disc herniation, and spinal stenosis, which... (Review)
Review
Intervertebral disc degeneration (IDD) causes a variety of signs and symptoms, such as low back pain (LBP), intervertebral disc herniation, and spinal stenosis, which contribute to high social and economic costs. IDD results from many factors, including genetic factors, aging, mechanical injury, malnutrition, and so on. The pathological changes of IDD are mainly composed of the senescence and apoptosis of nucleus pulposus cells (NPCs), the progressive degeneration of extracellular matrix (ECM), the fibrosis of annulus fibrosus (AF), and the inflammatory response. At present, IDD can be treated by conservative treatment and surgical treatment based on patients' symptoms. However, all of these can only release the pain but cannot reverse IDD and reconstruct the mechanical function of the spine. The latest research is moving towards the field of biotherapy. Mesenchymal stem cells (MSCs) are regard as the potential therapy of IDD because of their ability to self-renew and differentiate into a variety of tissues. Moreover, the non-coding RNAs (ncRNAs) are found to regulate many vital processes in IDD. There have been many successes in the in vitro and animal studies of using biotherapy to treat IDD, but how to transform the experimental data to real therapy which can apply to humans is still a challenge. This article mainly reviews the treatment strategies and research progress of IDD and indicates that there are many problems that need to be solved if the new biotherapy is to be applied to clinical treatment of IDD. This will provide reference and guidance for clinical treatment and research direction of IDD.
Topics: Animals; Annulus Fibrosus; Intervertebral Disc; Intervertebral Disc Degeneration; Intervertebral Disc Displacement; Mesenchymal Stem Cells; Nucleus Pulposus
PubMed: 35486489
DOI: 10.1111/os.13254 -
Autophagy Nov 2021Intervertebral disc degeneration (IDD) is the primary pathological mechanism that underlies low back pain. Overloading-induced cell death, especially endogenous stem...
Intervertebral disc degeneration (IDD) is the primary pathological mechanism that underlies low back pain. Overloading-induced cell death, especially endogenous stem cell death, is the leading factor that undermines intrinsic repair and aggravates IDD. Previous research has separately studied the effect of oxygen concentration and mechanical loading in IDD. However, how these two factors synergistically influence endogenous repair remains unclear. Therefore, we established and models to study the mechanisms by which hypoxia interacted with overloading-induced cell death of the nucleus pulposus derived stem cells (NPSCs). We found the content of HIF1A (hypoxia inducible factor 1 subunit alpha) and the number of NPSCs decreased with disc degeneration in both rats and human discs. Hence, we isolated this subpopulation from rat discs and treated them simultaneously with hypoxia and excessive mechanical stress. Our results demonstrated that hypoxia exerted protective effect on NPSCs under compression, partially through elevating macroautophagy/autophagy. Proteomics and knockdown experiments further revealed HIF1A-BNIP3-ATG7 axis mediated the increase in autophagy flux, in which HMOX1 and SLC2A1 were also involved. Moreover, HIF1A-overexpressing NPSCs exhibited stronger resistance to over-loading induced apoptosis . They also showed higher survival rates, along with elevated autophagy after being intra-disc transplanted into over-loaded discs. Jointly, both and experiments proved the anti-apoptotic effect of HIF1A on NPSCs under the excessive mechanical loading, suggesting that restoring hypoxia and manipulating autophagy is crucial to maintain the intrinsic repair and to retard disc degeneration. 3-MA: 3-methyladenine; ACAN: aggrecan; ATG7: autophagy related 7; BafA1: bafilomycin A; BAX: BCL2 associated X, apoptosis regulator; BECN1: beclin 1; BNIP3: BCL2 interacting protein 3; BNIP3L: BCL2 interacting protein 3 like; CASP3: caspase 3; CCK8: cell counting kit-8; CHT: chetomin; CMP: compression; CoCl: cobalt chloride; COL2A1: collagen type II alpha 1 chain; Ctrl: control; DAPI: 4,6-diamidino-2-phenylindole; DEP: differentially expressed protein; DiR: 1,1-dioctadecyl-3,3,3,3-tetramethyl indotricarbocyanine; ECM: extracellular matrix; FCM: flow cytometry; GD2: disialoganglioside GD 2; GFP: green fluorescent protein; GO: gene ontology; GSEA: gene set enrichment analysis; H&E: hematoxylin-eosin; HIF1A: hypoxia inducible factor 1 subunit alpha; HK2: hexokinase 2; HMOX1: heme oxygenase 1; HX: hypoxia mimicry; IDD: intervertebral disc degeneration; IF: immunofluorescence; IHC: immunohistochemistry; IVD: intervertebral disc; KEGG: kyoto encyclopedia of genes and genomes; LBP: low back pain; Lv: lentivirus; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MMP: mitochondrial membrane potential; NC: negative control; NIR: near-infrared; NP: nucleus pulposus; NPC: nucleus pulposus cell; NPSC: nucleus pulposus derived stem cell; NX: normoxia; PPI: protein-protein interactions; RFP: red fluorescent protein; SLC2A1/GLUT1: solute carrier family 2 member 1; SQSTM1/p62: sequestosome 1; TEK/TIE2: TEK receptor tyrosine kinase; TEM: transmission electron microscopy; TUBB: tubulin beta class I.
Topics: Animals; Apoptosis; Autophagy; Autophagy-Related Protein 7; Cell Hypoxia; Cells, Cultured; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Intervertebral Disc Degeneration; Membrane Proteins; Nucleus Pulposus; Protein Interaction Maps; Proto-Oncogene Proteins; Rats; Signal Transduction; Stem Cells; Stress, Mechanical
PubMed: 33455530
DOI: 10.1080/15548627.2021.1872227 -
Cell Proliferation Jul 2021Intervertebral disc degeneration (IDD) is a common clinical degenerative disease of the spine. A series of factors, such as inflammation, oxidative stress and mechanical... (Review)
Review
Intervertebral disc degeneration (IDD) is a common clinical degenerative disease of the spine. A series of factors, such as inflammation, oxidative stress and mechanical stress, promote degradation of the extracellular matrix (ECM) of the intervertebral discs (IVD), leading to dysfunction and structural destruction of the IVD. Nuclear factor-κB (NF-κB) transcription factor has long been regarded as a pathogenic factor of IDD. Therefore, NF-κB may be an ideal therapeutic target for IDD. As NF-κB is a multifunctional functional transcription factor with roles in a variety of biological processes, a comprehensive understanding of the function and regulatory mechanism of NF-κB in IDD pathology will be useful for the development of targeted therapeutic strategies for IDD, which can prevent the progression of IDD and reduce potential risks. This review discusses the role of the NF-κB signalling pathway in the nucleus pulposus (NP) in the process of IDD to understand pathological NP degeneration further and provide potential therapeutic targets that may interfere with NF-κB signalling for IDD therapy.
Topics: Epigenomics; Extracellular Matrix; Histone Deacetylases; Humans; Intervertebral Disc Degeneration; NF-kappa B; Nucleus Pulposus; Oxidative Stress; RNA, Untranslated; Signal Transduction
PubMed: 34028920
DOI: 10.1111/cpr.13057 -
Cell and Tissue Research Oct 2017The degradation of cartilage in the human body is impacted by aging, disease, genetic predisposition and continued insults resulting from daily activity. The burden of... (Review)
Review
The degradation of cartilage in the human body is impacted by aging, disease, genetic predisposition and continued insults resulting from daily activity. The burden of cartilage defects (osteoarthritis, rheumatoid arthritis, intervertebral disc damage, knee replacement surgeries, etc.) is daunting in light of substantial economic and social stresses. This review strives to broaden the scope of regenerative medicine and tissue engineering approaches used for cartilage repair by comparing and contrasting the anatomical and functional nature of the meniscus, articular cartilage (AC) and nucleus pulposus (NP). Many review papers have provided detailed evaluations of these cartilages and cartilage-like tissues individually but none have comprehensively examined the parallels and inconsistencies in signaling, genetic expression and extracellular matrix composition between tissues. For the first time, this review outlines the importance of understanding these three tissues as unique entities, providing a comparative analysis of anatomy, ultrastructure, biochemistry and function for each tissue. This novel approach highlights the similarities and differences between tissues, progressing research toward an understanding of what defines each tissue as distinctive. The goal of this paper is to provide researchers with the fundamental knowledge to correctly engineer the meniscus, AC and NP without inadvertently developing the wrong tissue function or biochemistry.
Topics: Animals; Biomechanical Phenomena; Cartilage, Articular; Collagen; Humans; Meniscus; Nucleus Pulposus; Regeneration; Tissue Engineering
PubMed: 28413859
DOI: 10.1007/s00441-017-2613-0 -
Molecular Therapy : the Journal of the... Oct 2022Abnormal mechanical load is a main risk factor of intervertebral disc degeneration (IDD), and cellular senescence is a pathological change in IDD. In addition,...
Abnormal mechanical load is a main risk factor of intervertebral disc degeneration (IDD), and cellular senescence is a pathological change in IDD. In addition, extracellular matrix (ECM) stiffness promotes human nucleus pulposus cells (hNPCs) senescence. However, the molecular mechanism underlying mechano-induced cellular senescence and IDD progression is not yet fully elucidated. First, we demonstrated that mechano-stress promoted hNPCs senescence via NF-κB signaling. Subsequently, we identified periostin as the main mechano-responsive molecule in hNPCs through unbiased sequencing, which was transcriptionally upregulated by NF-κB p65; moreover, secreted periostin by senescent hNPCs further promoted senescence and upregulated the catabolic process in hNPCs through activating NF-κB, forming a positive loop. Both Postn (encoding periostin) knockdown via siRNA and periostin inactivation via neutralizing antibodies alleviated IDD and NPCs senescence. Furthermore, we found that mechano-stress initiated the positive feedback of NF-κB and periostin via PIEZO1. PIEZO1 activation by Yoda1 induced severe IDD in rat tails without compression, and Postn knockdown alleviated the Yoda1-induced IDD in vivo. Here, we reported for the first time that self-amplifying loop of NF-κB and periostin initiated via PIEZO1 under mechano-stress accelerated NPCs senescence, leading to IDD. Furthermore, periostin neutralizing antibodies, which may serve as potential therapeutic agents for IDD, interrupted this loop.
Topics: Animals; Antibodies, Neutralizing; Cell Adhesion Molecules; Cellular Senescence; Humans; Intervertebral Disc Degeneration; Ion Channels; NF-kappa B; Nucleus Pulposus; RNA, Small Interfering; Rats
PubMed: 35619555
DOI: 10.1016/j.ymthe.2022.05.021 -
Frontiers in Immunology 2021Intervertebral disc (IVD) degeneration and its inflammatory microenvironment ultimately led to discogenic pain, which is thought to originate in the nucleus pulposus...
Intervertebral disc (IVD) degeneration and its inflammatory microenvironment ultimately led to discogenic pain, which is thought to originate in the nucleus pulposus (NP). In this study, key genes involved in NP tissue immune infiltration in lumbar disc herniation (LDH) were identified by bioinformatic analysis. Gene expression profiles were downloaded from the Gene Expression Omnibus (GEO) database. The CIBERSORT algorithm was used to analyze the immune infiltration into NP tissue between the LDH and control groups. Hub genes were identified by the WGCNA R package in Bioconductor and single-cell sequencing data was analyzed using R packages. Gene expression levels were evaluated by quantitative real-time polymerase chain reaction. The immune infiltration profiles varied significantly between the LDH and control groups. Compared with control tissue, LDH tissue contained a higher proportion of regulatory T cells and macrophages, which are associated with the macrophage polarization process. The most significant module contained three hub genes and four subclusters of NP cells. Functional analysis of these genes was performed, the hub gene expression pattern was confirmed by PCR, and clinical features of the patients were investigated. Finally, we identified TGF-β and MAPK signaling pathways as crucial in this process and these pathways may provide diagnostic markers for LDH. We hypothesize that the hub genes expressed in the specific NP subclusters, along with the infiltrating macrophages play important roles in the pathogenesis of IVD degeneration and ultimately, disc herniation.
Topics: Biomarkers; Cytokines; Databases, Genetic; Female; Gene Expression; Gene Regulatory Networks; Humans; Intervertebral Disc Degeneration; Intervertebral Disc Displacement; Macrophages; Male; Nucleus Pulposus; Prognosis; Single-Cell Analysis; T-Lymphocytes, Regulatory
PubMed: 34122424
DOI: 10.3389/fimmu.2021.666355 -
Journal of Nanobiotechnology Sep 2021Exosome therapy is a promising therapeutic approach for intervertebral disc degeneration (IVDD) and achieves its therapeutic effects by regulating metabolic disorders,...
Exosome therapy is a promising therapeutic approach for intervertebral disc degeneration (IVDD) and achieves its therapeutic effects by regulating metabolic disorders, the microenvironment and cell homeostasis with the sustained release of microRNAs, proteins, and transcription factors. However, the rapid clearance and disruption of exosomes are the two major challenges for the application of exosome therapy in IVDD. Herein, a thermosensitive acellular extracellular matrix (ECM) hydrogel coupled with adipose-derived mesenchymal stem cell (ADSC) exosomes (dECM@exo) that inherits the superior properties of nucleus pulposus tissue and ADSCs was fabricated to ameliorate IVDD. This thermosensitive dECM@exo hydrogel system can provide not only in situ gelation to replenish ECM leakage in nucleus pulposus cells (NPCs) but also an environment for the growth of NPCs. In addition, sustained release of ADSC-derived exosomes from this system regulates matrix synthesis and degradation by regulating matrix metalloproteinases (MMPs) and inhibits pyroptosis by mitigating the inflammatory response in vitro. Animal results demonstrated that the dECM@exo hydrogel system maintained early IVD microenvironment homeostasis and ameliorated IVDD. This functional system can serve as a powerful platform for IVD drug delivery and biotherapy and an alternative therapy for IVDD.
Topics: Animals; Exosomes; Extracellular Matrix; Humans; Hydrogels; Intervertebral Disc Degeneration; Male; Matrix Metalloproteinase 13; Mesenchymal Stem Cells; MicroRNAs; Nucleus Pulposus; Pyroptosis; Rats; Tissue Engineering
PubMed: 34488795
DOI: 10.1186/s12951-021-00991-5 -
Experimental & Molecular Medicine Jul 2022Intervertebral disc degeneration (IVDD) is a major cause of low back pain (LBP), and excessive senescence and apoptosis of nucleus pulposus (NP) cells are major...
Intervertebral disc degeneration (IVDD) is a major cause of low back pain (LBP), and excessive senescence and apoptosis of nucleus pulposus (NP) cells are major pathological changes in IVDD. Physical exercise could effectively delay the process of intervertebral disc degeneration; however, its mechanism is still largely unknown. Irisin is an exercise-induced myokine released upon cleavage of the membrane-bound precursor protein fibronectin type III domain-containing protein 5 (FNDC5), and its levels increase after physical exercise. Here, we show that after physical exercise, FNDC5/irisin levels increase in the circulation and NP, senescence and apoptosis are reduced, autophagy is activated in NP tissue, and the progression of IVDD is delayed. Conversely, after knocking out FNDC5, the benefits of physical exercise are compromised. Moreover, the overexpression of FNDC5 in NP tissue effectively alleviated the degeneration of the intervertebral disc (IVD) in rats. By showing that FNDC5/irisin is an important mediator of the beneficial effects of physical exercise in the IVDD model, the study proposes FNDC5/irisin as a novel agent capable of activating autophagy and protecting NP from senescence and apoptosis.
Topics: Animals; Apoptosis; Autophagy; Fibronectins; Intervertebral Disc Degeneration; Mice; Nucleus Pulposus; Rats; Swimming; Transcription Factors
PubMed: 35882943
DOI: 10.1038/s12276-022-00811-2 -
Nature Communications Sep 2021Intervertebral disc degeneration is highly prevalent within the elderly population and is a leading cause of chronic back pain and disability. Due to the link between...
Intervertebral disc degeneration is highly prevalent within the elderly population and is a leading cause of chronic back pain and disability. Due to the link between disc degeneration and senescence, we explored the ability of the Dasatinib and Quercetin drug combination (D + Q) to prevent an age-dependent progression of disc degeneration in mice. We treated C57BL/6 mice beginning at 6, 14, and 18 months of age, and analyzed them at 23 months of age. Interestingly, 6- and 14-month D + Q cohorts show lower incidences of degeneration, and the treatment results in a significant decrease in senescence markers p16, p19, and SASP molecules IL-6 and MMP13. Treatment also preserves cell viability, phenotype, and matrix content. Although transcriptomic analysis shows disc compartment-specific effects of the treatment, cell death and cytokine response pathways are commonly modulated across tissue types. Results suggest that senolytics may provide an attractive strategy to mitigating age-dependent disc degeneration.
Topics: Aggrecans; Aging; Animals; Annulus Fibrosus; Cell Survival; Cellular Senescence; Dasatinib; Extracellular Matrix; Fibrosis; Inflammation; Intervertebral Disc Degeneration; Mice; Mice, Inbred C57BL; Nucleus Pulposus; Phenotype; Quercetin; Transcriptome
PubMed: 34480023
DOI: 10.1038/s41467-021-25453-2 -
Advanced Science (Weinheim,... Jan 2022Although degeneration of the nucleus pulposus (NP) is a major contributor to intervertebral disc degeneration (IVDD) and low back pain, the underlying molecular...
Although degeneration of the nucleus pulposus (NP) is a major contributor to intervertebral disc degeneration (IVDD) and low back pain, the underlying molecular complexity and cellular heterogeneity remain poorly understood. Here, a comprehensive single-cell resolution transcript landscape of human NP is reported. Six novel human NP cells (NPCs) populations are identified by their distinct molecular signatures. The potential functional differences among NPC subpopulations are analyzed. Predictive transcripts, transcriptional factors, and signal pathways with respect to degeneration grades are explored. It is reported that fibroNPCs is the subpopulation for end-stage degeneration. CD90+NPCs are observed to be progenitor cells in degenerative NP tissues. NP-infiltrating immune cells comprise a previously unrecognized diversity of cell types, including granulocytic myeloid-derived suppressor cells (G-MDSCs). Integrin αM (CD11b) and oxidized low density lipoprotein receptor 1 (OLR1) as surface markers of NP-derived G-MDSCs are uncovered. The G-MDSCs are found to be enriched in mildly degenerated (grade II and III) NP tissues compared to severely degenerated (grade IV and V) NP tissues. Their immunosuppressive function and alleviation effects on NPCs' matrix degradation are revealed in vitro. Collectively, this study reveals the NPC-type complexity and phenotypic characteristics in NP, thereby providing new insights and clues for IVDD treatment.
Topics: Female; Gene Expression Profiling; Humans; Intervertebral Disc; Intervertebral Disc Degeneration; Male; Middle Aged; Nucleus Pulposus; Signal Transduction; Stem Cells
PubMed: 34825784
DOI: 10.1002/advs.202103631