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1.
Eur Rev Med Pharmacol Sci ; 26(8): 2990-3000, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-35503599

RESUMEN

OBJECTIVE: Recent evidence suggests that statins, among lipid-lowering drugs, can be used to lower serum cholesterol levels for reducing the risk of cardiovascular disease in individuals with high cholesterol, as well as reducing DNA damage and having anti-ageing and pleiotropic effects. Additionally, nuclear factor kappa B (NF-κB) is reported to be suppressed in statin-administered nucleus pulposus (NP) cells for the prevention of interleukin (IL) -1 beta (IL-1ß)-induced apoptosis and extracellular matrix (ECM) degradation. The purpose of this study is the examine whether it is possible for pharmacological synthetic statin agents added into primary cell cultures obtained from human intervertebral disc tissue (IVD) to stop and eliminate tissue degeneration through the anabolic/catabolic signaling pathways associated with inflammation. MATERIALS AND METHODS: Pitavastatin and rosuvastatin were added to monolayer grown human primary annulus fibrosus (AF)/NP cells. Cytotoxicity and proliferation analyses were carried out. AF/NP cells and ECM structure were also examined microscopically. In addition, changes in transcription factors and protein expressions of proinflammatory cytokines, which play important roles in anabolic and catabolic pathways associated with inflammation, were analyzed. RESULTS: Decreased proliferation and cell necrosis were observed at the end of 72 hours in the samples, in which statins were added, compared to the samples in the control group to which no pharmacological agent was administered. In addition to this, changes were observed in the expressions of proteins. All results were statistically significant (p<0.05). CONCLUSIONS: To better understand the regenerative effects of these two pharmacological agents on degenerated AF/NP cells, there is an urgent need for prospective studies in which different signaling pathways and receptors on these pathways are investigated, apart from IL-1ß; NF-κB signaling pathway and SOX9.


Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas , Degeneración del Disco Intervertebral , Disco Intervertebral , Núcleo Pulposo , Células Cultivadas , Colesterol , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Inflamación/metabolismo , Interleucina-1beta/metabolismo , Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/metabolismo , FN-kappa B/metabolismo , Núcleo Pulposo/metabolismo , Estudios Prospectivos , Transducción de Señal
2.
Bioengineered ; 13(5): 11684-11693, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-35506157

RESUMEN

As a multifactorial disease, intervertebral disc degeneration (IVDD) causes many spinal-related diseases, which causes disability in the workforce and heavy social costs all over the world. Recently, Ganoderic Acid A (GAA) has been reported to play many pharmacological effects. However, its effect on IVDD remains unclear. In the present study, our study determined that GAA significantly inhibited H2O2 induced apoptosis, release of inflammatory cytokines and oxidative stress mediators in the nucleus pulposus (NP) cells. Moreover, GAA also suppressed H2O2 induced major matrix degrading proteases (MMP-3, MMP-13, ADAMTS4 and ADAMTS5) associated with NP degradation. Additionally, we found NP protective ability of GAA by up-regulating extra cellular matrix anabolic factors like type II collagen (Col II) and aggrecan in NP cells. Furthermore, we also demonstrated that GAA suppressed the activation of TLR4/NLRP3 in H2O2-stimulated NP cells. Thus, our results demonstrate that GAA inhibited the H2O2 induced apoptosis, oxidative stress, and inflammatory responses through the depression of TLR4/NLRP3 signaling axis. GAA possess NP protective properties and may be of value in suppressing the pathogenesis of IVDD.


Asunto(s)
Degeneración del Disco Intervertebral , Disco Intervertebral , Animales , Ácidos Heptanoicos , Peróxido de Hidrógeno/farmacología , Disco Intervertebral/metabolismo , Disco Intervertebral/patología , Degeneración del Disco Intervertebral/tratamiento farmacológico , Lanosterol/análogos & derivados , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Receptor Toll-Like 4
3.
Oxid Med Cell Longev ; 2022: 1045999, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35528509

RESUMEN

Purpose: The pathological role of axial stress in intervertebral disc degeneration (IDD) is controversial, and there was no quantified study until now. Here, we tried to clarify the correlation between IDD or low back pain (LBP) and axial stress at different duration and magnitude in vitro and in vivo. Method: In vitro, the gene expression of aggrecan, matrix metalloproteinase-3 (MMP3), calcitonin gene-related peptide (CGRP), and substance P (SP) was measured when nucleus pulposus cells (NPCs) were compressed under gradual severity. In vivo, a measurable Ilizarov-type compression apparatus was established for single coccygeal (Co) intervertebral disc (IVD) compression of Co7-8 in mouse. Gradient stress was placed at 0.4 Mpa (mild), 0.8 Mpa (moderate), and 1.2 Mpa (severe) for three days to investigate the effect of the magnitude of axial stress. Additionally, mild compression with 3, 7, and 14 days was used to determine the effect of the duration of axial stress. Subsequently, we evaluated the severity of IDD and LBP by radiological X-ray film; histological examination with H&E staining; immunohistochemical analysis with collagen II, aggrecan, and CGRP staining; and western blot analysis with collagen II, aggrecan, MMP-3, and interleukin-1ß (IL-1ß). Results: When NPCs suffered gradual increased mechanical stress, the cells exhibited gradual downregulated expression of extracellular matrix (ECM)-related gene of aggrecan, upregulated expression of IDD-related gene of MMP3, and LBP-related gene of CGRP and SP. In the meantime, with different magnitudes of axial stress, the IVD showed progressively severe IDD and LBP, with gradual narrowing intervertebral height, destruction of IVD anatomy, decreased ECM, and increased catabolic factors and proalgesic peptides. Conclusion: Axial compression is one of the critical pathological factors to cause IDD and LBP, and there was a strong positive correlation depended on the duration and magnitude of compression.


Asunto(s)
Degeneración del Disco Intervertebral , Disco Intervertebral , Dolor de la Región Lumbar , Agrecanos/genética , Animales , Péptido Relacionado con Gen de Calcitonina/metabolismo , Colágeno/metabolismo , Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/patología , Metaloproteinasa 3 de la Matriz/metabolismo , Ratones
4.
Biosens Bioelectron ; 210: 114346, 2022 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-35569268

RESUMEN

Measurement of macrophage activation and its modulation for immune regulation is of great interest to arrest inflammatory responses associated with degeneration of intervertebral discs that cause chronic back pain, and with transplants that face immune rejection. Due to the phenotypic plasticity of macrophages that serve multiple immune functions, the net disease outcome is determined by a balance of subpopulations with competing functions, highlighting the need for single-cell methods to quantify heterogeneity in their activation phenotypes. However, since macrophage activation can follow several signaling pathways, cytometry after fluorescent staining of markers with antibodies does not often provide dose-dependent information on activation dynamics. We present high throughput single-cell impedance cytometry for multiparametric measurement of biophysical changes to individual macrophages for quantifying activation in a dose and duration dependent manner, without relying on a particular signaling pathway. Impedance phase metrics measured at two frequencies and the electrical diameter from impedance magnitude at lower frequencies are used in tandem to benchmark macrophage activation by degenerated discs against that from lipopolysaccharide stimulation at varying dose and duration levels, so that reversal of the activation state by curcumin can be ascertained. This label-free single-cell measurement method can form the basis for platforms to screen therapies for inflammation, thereby addressing the chronic problem of back pain.


Asunto(s)
Técnicas Biosensibles , Degeneración del Disco Intervertebral , Disco Intervertebral , Impedancia Eléctrica , Humanos , Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/tratamiento farmacológico , Degeneración del Disco Intervertebral/metabolismo , Activación de Macrófagos
5.
Int J Mol Sci ; 23(7)2022 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-35409356

RESUMEN

In this study, we used single-cell transcriptomic analysis to identify new specific biomarkers for nucleus pulposus (NP) and inner annulus fibrosis (iAF) cells, and to define cell populations within non-degenerating (nD) and degenerating (D) human intervertebral discs (IVD) of the same individual. Cluster analysis based on differential gene expression delineated 14 cell clusters. Gene expression profiles at single-cell resolution revealed the potential functional differences linked to degeneration, and among NP and iAF subpopulations. GO and KEGG analyses discovered molecular functions, biological processes, and transcription factors linked to cell type and degeneration state. We propose two lists of biomarkers, one as specific cell type, including C2orf40, MGP, MSMP, CD44, EIF1, LGALS1, RGCC, EPYC, HILPDA, ACAN, MT1F, CHI3L1, ID1, ID3 and TMED2. The second list proposes predictive IVD degeneration genes, including MT1G, SPP1, HMGA1, FN1, FBXO2, SPARC, VIM, CTGF, MGST1, TAF1D, CAPS, SPTSSB, S100A1, CHI3L2, PLA2G2A, TNRSF11B, FGFBP2, MGP, SLPI, DCN, MT-ND2, MTCYB, ADIRF, FRZB, CLEC3A, UPP1, S100A2, PRG4, COL2A1, SOD2 and MT2A. Protein and mRNA expression of MGST1, vimentin, SOD2 and SYF2 (p29) genes validated our scRNA-seq findings. Our data provide new insights into disc cells phenotypes and biomarkers of IVD degeneration that could improve diagnostic and therapeutic options.


Asunto(s)
Quitinasas , Proteínas F-Box , Degeneración del Disco Intervertebral , Disco Intervertebral , Núcleo Pulposo , Biomarcadores/metabolismo , Proteínas de Ciclo Celular/metabolismo , Quitinasas/metabolismo , Proteínas F-Box/genética , Humanos , Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/genética , Degeneración del Disco Intervertebral/metabolismo , Lectinas Tipo C/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Núcleo Pulposo/metabolismo , Análisis de Secuencia de ARN
6.
Int J Mol Sci ; 23(7)2022 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-35409417

RESUMEN

Intervertebral disc (IVD) diseases are common spinal disorders that cause neck or back pain in the presence or absence of an underlying neurological disorder. IVD diseases develop on the basis of degeneration, and there are no established treatments for degeneration. IVD diseases may therefore represent a candidate for the application of regenerative medicine, potentially employing normal human dermal fibroblasts (NHDFs) induced to differentiate into nucleus pulposus (NP) cells. Here, we used a three-dimensional culture system to demonstrate that ectopic expression of MYC, KLF4, NOTO, SOX5, SOX6, and SOX9 in NHDFs generated NP-like cells, detected using Safranin-O staining. Quantitative PCR, microarray analysis, and fluorescence-activated cell sorting revealed that the induced NP cells exhibited a fully differentiated phenotype. These findings may significantly contribute to the development of effective strategies for treating IVD diseases.


Asunto(s)
Degeneración del Disco Intervertebral , Disco Intervertebral , Núcleo Pulposo , Fibroblastos/metabolismo , Humanos , Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/terapia , Desplazamiento del Disco Intervertebral , Núcleo Pulposo/metabolismo
7.
Oxid Med Cell Longev ; 2022: 9731800, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35464773

RESUMEN

A healthy microenvironment of the intervertebral disc tissue is characterized by hypoxia owing to its sparse vascular distribution. Oxidative stress plays a pivotal role in the pathological development of intervertebral disc degeneration (IVDD). We found that the expression of prolyl endopeptidase (PREP) increased in degenerative nucleus pulposus (NP) tissues. The purpose of this study was to determine whether PREP is involved in oxidative-stress-induced IVDD. Tertbutyl hydroperoxide can inhibit the expression of PREP by activating the PI3K/AKT signaling pathway at low concentrations in NP cells. Knockdown of PREP protected NP cells from apoptosis induced by oxidative stress, whereas overexpression of PREP exacerbated the apoptosis of NP cells. We also investigated the connection between the PI3K/AKT signaling pathway and PREP and found that the activation of the PI3K/AKT signaling pathway downregulated the expression of PREP by inhibiting p53. As a crucial transcription factor, p53 binds to the PREP promoter region and promotes its transcription. Overexpression of PREP also impairs protein secretion in the extracellular matrix of NP cells. Furthermore, the in vivo knockout of PREP could attenuate puncture-induced IVDD. These findings suggested that the downregulation of PREP might maintain the viability of NP cells and attenuate IVDD under oxidative stress.


Asunto(s)
Degeneración del Disco Intervertebral , Disco Intervertebral , Núcleo Pulposo , Apoptosis/fisiología , Humanos , Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/patología , Núcleo Pulposo/patología , Estrés Oxidativo , Fosfatidilinositol 3-Quinasas/metabolismo , Prolil Oligopeptidasas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteína p53 Supresora de Tumor/metabolismo
8.
Oxid Med Cell Longev ; 2022: 2239770, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35401932

RESUMEN

Oxidative stress has been proved to play important roles in the development of intervertebral disc degeneration (IDD); however, the underlying mechanism remains obscure to date. The aim of this study was to elucidate the vital roles of oxidative stress-related genes in the development of IDD using strict bioinformatic algorithms. The microarray data relevant to the IDD was downloaded from Gene Expression Omnibus database for further analysis. A series of bioinformatic strategies were used to determine the oxidative stress-related and IDD-related genes (OSIDDRGs), perform the function enrichment analysis and protein-protein interaction analysis, construct the lncRNA-miRNA-mRNA regulatory network, and investigate the potential relationship of oxidative stress to immunity abnormality and autophagy in IDD. We observed a significantly different status of oxidative stress between normal intervertebral disc tissues and IDD tissues. A total of 72 OSIDDRGs were screened out for the further function enrichment analysis, and 10 hub OSIDDRGs were selected to construct the lncRNA-miRNA-mRNA regulatory network. There was a very close association of oxidative stress with immunity abnormality and autophagy in IDD. Taken together, our findings can provide new insights into the mechanism research of oxidative stress in the development of IDD and offer new potential targets for the treatment strategies.


Asunto(s)
Degeneración del Disco Intervertebral , Disco Intervertebral , MicroARNs , ARN Largo no Codificante , Biología Computacional , Humanos , Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/genética , Degeneración del Disco Intervertebral/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Estrés Oxidativo/genética , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo
9.
Int J Mol Sci ; 23(7)2022 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-35409374

RESUMEN

Previous research has identified an association between external radiation and disc degeneration, but the mechanism was poorly understood. This study explores the effects of ionizing radiation (IR) on inducing cellular senescence of annulus fibrosus (AF) in cell culture and in an in vivo mouse model. Exposure of AF cell culture to 10-15 Gy IR for 5 min followed by 5 days of culture incubation resulted in almost complete senescence induction as evidenced by SA-ßgal positive staining of cells and elevated mRNA expression of the p16 and p21 senescent markers. IR-induced senescent AF cells exhibited increased matrix catabolism, including elevated matrix metalloproteinase (MMP)-1 and -3 protein expression and aggrecanolysis. Analogous results were seen with whole body IR-exposed mice, demonstrating that genotoxic stress also drives disc cellular senescence and matrix catabolism in vivo. These results have important clinical implications in the potential adverse effects of ionizing radiation on spinal health.


Asunto(s)
Anillo Fibroso , Degeneración del Disco Intervertebral , Disco Intervertebral , Animales , Anillo Fibroso/metabolismo , Senescencia Celular , Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/genética , Degeneración del Disco Intervertebral/metabolismo , Metaloproteinasas de la Matriz/metabolismo , Ratones , Radiación Ionizante
10.
Front Biosci (Landmark Ed) ; 27(4): 131, 2022 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-35468690

RESUMEN

BACKGROUND: The defect of intervertebral disc (IVD) after discectomy may impair tissue healing and predispose patients to subsequent IVD degeneration, which is thought to be an important cause of recurrence. Cell-based approaches for the treatment of IVD degeneration have shown promise in preclinical studies. However, most of these therapies have not been approved for clinical use due to the risks of abnormal differentiation and microorganism contamination of the culture-expanded cells. Selective cell retention (SCR) technology is non-cultivation technique, which can avoid those preambles in cell expansion. In this study, we used a commercially available BONE GROWTH PROMOTER device (BGP, FUWOSI, Chongqing, China) to concentrate mesenchymal stromal cells (MSCs) from bone marrow aspirate (BMA) through SCR technology. METHODS: A small incision was made on the L2/3, L3/4 and L4/5 discs of goats and part of nucleus pulposus (NP) was removed to construct IVD defect model. The L2/3 disc was subjected to discectomy only (DO group), the L3/4 disc was implanted with enriched BMA-matrix (CE group), and the L4/5 disc was implanted cultured autologous bone marrow MSCs matrix (CC group). And the intact L1/2 disc served as a non-injured control (NC group). The animals were followed up for 24 weeks after operation. Spine imaging was analysis performed at 4 and 24 weeks. Histology, immunohistochemistry, gene expression and biomechanical analysis were performed to investigate the IVD morphology, content and mechanical properties at 24 weeks. RESULTS: The CE and CC groups showed a significantly smaller reduction in the disc height and T2-weighted signal intensity, and a better spinal segmental stability than DO group. Histological analysis demonstrated that CE and CC groups maintained a relatively well-preserved structure compared to the DO group. Furthermore, real-time PCR and immunohistochemistry demonstrated that aggrecan and type II collagen were up-regulated in CE and CC groups compared to DO group. CONCLUSIONS: The strategy of MSCs enrichment combined with gelatin sponge by SCR technology provides a rapid, simple, and effective method for cell concentration and cell-carrier combination. This reparative strategy can be used in clinical treatment of IVD defect after discectomy. CLINICAL TRIAL REGISTRATION: NCT03002207.


Asunto(s)
Degeneración del Disco Intervertebral , Disco Intervertebral , Células Madre Mesenquimatosas , Animales , Discectomía/efectos adversos , Gelatina/metabolismo , Cabras , Humanos , Disco Intervertebral/metabolismo , Disco Intervertebral/patología , Disco Intervertebral/cirugía , Degeneración del Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/cirugía
11.
Aging Cell ; 21(4): e13577, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-35266272

RESUMEN

Rejuvenation of nucleus pulposus cells (NPCs) in degenerative discs can reverse intervertebral disc degeneration (IDD). Partial reprogramming is used to rejuvenate aging cells and ameliorate progression of aging tissue to avoiding formation of tumors by classical reprogramming. Understanding the effects and potential mechanisms of partial reprogramming in degenerative discs provides insights for development of new therapies for IDD treatment. The findings of the present study show that partial reprogramming through short-term cyclic expression of Oct-3/4, Sox2, Klf4, and c-Myc (OSKM) inhibits progression of IDD, and significantly reduces senescence related phenotypes in aging NPCs. Mechanistically, short-term induction of OSKM in aging NPCs activates energy metabolism as a "energy switch" by upregulating expression of Hexokinase 2 (HK2) ultimately promoting redistribution of cytoskeleton and restoring the aging state in aging NPCs. These findings indicate that partial reprogramming through short-term induction of OSKM has high therapeutic potential in the treatment of IDD.


Asunto(s)
Degeneración del Disco Intervertebral , Disco Intervertebral , Núcleo Pulposo , Reprogramación Celular , Humanos , Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/metabolismo , Núcleo Pulposo/metabolismo , Rejuvenecimiento
12.
Mol Med Rep ; 25(5)2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-35315494

RESUMEN

Previous studies have indicated that chronic intermittent hypobaric hypoxia (CIHH) preconditioning can inhibit TNF­α and other related inflammatory cytokines and exerts protective effect on intervertebral disc degeneration disease (IDD) in rats; however, the mechanism is still unclear. The present study aimed to explore the repair mechanisms of CIHH on IDD in rats. In the experiment, 48 adult Sprague­Dawley rats were selected and randomly divided into an experimental group (CIHH­IDD), a degenerative group (IDD) and a control group (CON). The CIHH­IDD group of rats (n=16) were treated with CIHH (simulated 3000 m altitude, 5 h per day, 28 days; PO2=108.8 mmHg) before disc degeneration surgery. The IDD group of rats (n=16) underwent tail­vertebral intervertebral disc surgery to establish a model of intervertebral disc degeneration. The CON group of rats (n=16) did not receive any treatments. After surgery, the disc height index was calculated using X­ray analysis of rat tail vertebrae, the degeneration process was observed and repair was evaluated by chemically staining degenerative intervertebral disc tissue slices. The expression levels of basic fibroblast growth factor (bFGF), TGFß1, Collagen I and Collagen II were measured in the intervertebral disc tissue using western blotting; while the expression levels of bFGF, TGFß1 and hypoxia­inducible factor 1­α (HIF­1α) were measured in rat serum using ELISA. The results demonstrated that: i) The degree of intervertebral disc height degeneration in CIHH­IDD rats was significantly lower compared with that in IDD rats (P<0.05); ii) the expression levels of bFGF, TGFß1 and HIF­1α were higher in CIHH­IDD rat serum compared with those in IDD rat serum (P<0.05); iii) optical microscopy revealed that the degree of disc degeneration was relatively mild in CIHH­IDD rats; and iv) the protein expression levels of bFGF, TGFß1 and collagen II were increased in CIHH­IDD rat intervertebral disc tissues compared with those of IDD rats, while the overexpression of collagen I protein was inhibited. Overall, after CIHH pre­treatment, the expression levels of bFGF and TGFß1 were up­regulated, which play notable roles in repairing degenerative intervertebral discs in rats.


Asunto(s)
Degeneración del Disco Intervertebral , Disco Intervertebral , Animales , Colágeno/metabolismo , Hipoxia/metabolismo , Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/terapia , Ratas , Ratas Sprague-Dawley
13.
Aging (Albany NY) ; 14(5): 2400-2417, 2022 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-35289767

RESUMEN

With the increasing burden of a globally aging population, low back pain has become one of the most common musculoskeletal disorders, caused mainly by intervertebral disc (IVD) degeneration. There are currently several clinical methods to alleviate back pain, but there is scarce attention paid as to whether they can improve age-related IVD degeneration. It is therefore difficult to conduct an in-depth evaluation of these methods. A large number of clinical studies have shown that manual therapy (MT), a widely used comprehensive alternative method, has effects on pain, the mechanisms of which require further study. In this study, MT was performed on aging rats for 6 months, and their behaviors were compared with those of a non-intervention group of aging and young rats. After the intervention, all rats were examined by X-ray to observe lumbar spine degeneration, and the IVD tissues were dissected for detection, including pathological staining, immunofluorescence, Western bolt, etc. This study demonstrated the possibility that MT intervention delay the lumbar IVD degeneration in aging rats, specifically improving the motor function and regulating senescence-associated ß-galactosidase, p53, p21, p16, and telomerase activity to retard the senescence of cells in IVDs. Moreover, MT intervention can modify oxidative stress, increase the expression of SIRT1 and FOXO1 in IVDs and decrease ac-FOXO1 expression, suggesting that MT can reduce oxidative stress through the SIRT1/FOXO1 pathway, thereby playing a role in delaying the aging of IVDs. This study shows that drug-free, non-invasive mechanical interventions could be of major significance in improving the physical function of the elderly.


Asunto(s)
Degeneración del Disco Intervertebral , Disco Intervertebral , Manipulaciones Musculoesqueléticas , Envejecimiento , Animales , Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Estrés Oxidativo , Ratas , Sirtuina 1/metabolismo
14.
Nat Commun ; 13(1): 1469, 2022 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-35304463

RESUMEN

N6-methyladenosine (m6A) is the most prevalent RNA modification at the posttranscriptional level and involved in various diseases and cellular processes. However, the underlying mechanism of m6A regulation in intervertebral disc degeneration (IVDD) remains elusive. Here, we show that methylation of the lncRNA NORAD significantly increases in senescent nucleus pulposus cells (NPCs) by m6A sequencing. Subsequent loss- and gain-of-function experiments reveal WTAP is increased in senescent NPCs due to an epigenetic increase in H3K4me3 of the promoter mediated by KDM5a, and significantly promotes NORAD m6A modification. Furthermore, YTHDF2-mediated decay of NORAD is enhanced in senescent NPCs, and then deficiency of NORAD results in less sequestraion of PUMILIO proteins, contributing to the augmented activity of PUM1/2, thus repressing the expression of target E2F3 mRNAs and promoting the cellular senescence. Here, we show interruption of NORAD m6A modification or the NORAD/PUMILIO/E2F3 axis could serve as a potential therapeutic target to inhibit the senescence of NPCs and development of IVDD.


Asunto(s)
Degeneración del Disco Intervertebral , Disco Intervertebral , Núcleo Pulposo , ARN Largo no Codificante , Proteínas de Ciclo Celular/metabolismo , Senescencia Celular/genética , Humanos , Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/metabolismo , Núcleo Pulposo/metabolismo , Factores de Empalme de ARN/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Proteína 2 de Unión a Retinoblastoma/metabolismo
15.
Int J Mol Sci ; 23(6)2022 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-35328395

RESUMEN

Animal studies suggest that pain-related-molecule upregulation in degenerated intervertebral discs (IVDs) potentially leads to low back pain (LBP). We hypothesized that IVD mechanical stress and axial loading contribute to discogenic LBP's pathomechanism. This study aimed to elucidate the relationships among the clinical findings, radiographical findings, and pain-related-molecule expression in human degenerated IVDs. We harvested degenerated-IVD samples from 35 patients during spinal interbody fusion surgery. Pain-related molecules including tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6, calcitonin gene-related peptide (CGRP), microsomal prostaglandin E synthase-1 (mPGES1), and nerve growth factor (NGF) were determined. We also recorded preoperative clinical findings including body mass index (BMI), Oswestry Disability Index (ODI), and radiographical findings including the vacuum phenomenon (VP) and spinal instability. Furthermore, we compared pain-related-molecule expression between the VP (-) and (+) groups. BMI was significantly correlated with the ODI, CGRP, and mPGES-1 levels. In the VP (+) group, mPGES-1 levels were significantly higher than in the VP (-) group. Additionally, CGRP and mPGES-1 were significantly correlated. Axial loading and mechanical stress correlated with CGRP and mPGES-1 expression and not with inflammatory cytokine or NGF expression. Therefore, axial loading and mechanical stress upregulate CGRP and mPGES-1 in human degenerated IVDs, potentially leading to chronic discogenic LBP.


Asunto(s)
Degeneración del Disco Intervertebral , Disco Intervertebral , Dolor de la Región Lumbar , Animales , Índice de Masa Corporal , Péptido Relacionado con Gen de Calcitonina/metabolismo , Humanos , Interleucina-6/metabolismo , Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/metabolismo , Dolor de la Región Lumbar/etiología , Factor de Crecimiento Nervioso/metabolismo , Vacio
16.
Int J Mol Sci ; 23(5)2022 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-35269863

RESUMEN

Low back pain (LBP) has been among the leading causes of disability for the past 30 years. This highlights the need for improvement in LBP management. Many clinical trials focus on developing treatments against degenerative disc disease (DDD). The multifactorial etiology of DDD and associated risk factors lead to a heterogeneous patient population. It comes as no surprise that the outcomes of clinical trials on intradiscal mesenchymal stem cell (MSC) injections for patients with DDD are inconsistent. Intradiscal MSC injections have demonstrated substantial pain relief and significant disability-related improvements, yet they have failed to regenerate the intervertebral disc (IVD). Increasing evidence suggests that the positive outcomes in clinical trials might be attributed to the immunomodulatory potential of MSCs rather than to their regenerative properties. Therefore, patient stratification for inflammatory DDD phenotypes may (i) better serve the mechanisms of action of MSCs and (ii) increase the treatment effect. Modic type 1 changes-pathologic inflammatory, fibrotic changes in the vertebral bone marrow-are frequently observed adjacent to degenerated IVDs in chronic LBP patients and represent a clinically distinct subpopulation of patients with DDD. This review discusses whether degenerated IVDs of patients with Modic type 1 changes should be treated with an intradiscal MSC injection.


Asunto(s)
Degeneración del Disco Intervertebral , Disco Intervertebral , Dolor de la Región Lumbar , Células Madre Mesenquimatosas , Médula Ósea/metabolismo , Humanos , Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/metabolismo , Dolor de la Región Lumbar/etiología , Dolor de la Región Lumbar/terapia , Células Madre Mesenquimatosas/metabolismo
17.
Nat Commun ; 13(1): 634, 2022 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-35110524

RESUMEN

Back pain is a common and debilitating disorder with largely unknown underlying biology. Here we report a genome-wide association study of back pain using diagnoses assigned in clinical practice; dorsalgia (119,100 cases, 909,847 controls) and intervertebral disc disorder (IDD) (58,854 cases, 922,958 controls). We identify 41 variants at 33 loci. The most significant association (ORIDD = 0.92, P = 1.6 × 10-39; ORdorsalgia = 0.92, P = 7.2 × 10-15) is with a 3'UTR variant (rs1871452-T) in CHST3, encoding a sulfotransferase enzyme expressed in intervertebral discs. The largest effects on IDD are conferred by rare (MAF = 0.07 - 0.32%) loss-of-function (LoF) variants in SLC13A1, encoding a sodium-sulfate co-transporter (LoF burden OR = 1.44, P = 3.1 × 10-11); variants that also associate with reduced serum sulfate. Genes implicated by this study are involved in cartilage and bone biology, as well as neurological and inflammatory processes.


Asunto(s)
Degeneración del Disco Intervertebral/genética , Desplazamiento del Disco Intervertebral/genética , Disco Intervertebral/metabolismo , Cotransportador de Sodio-Sulfato/genética , Cotransportador de Sodio-Sulfato/metabolismo , Sulfatos/metabolismo , Regiones no Traducidas 3' , Huesos/metabolismo , Estudio de Asociación del Genoma Completo , Humanos , Simportadores/genética , Simportadores/metabolismo
18.
Biomed Pharmacother ; 148: 112739, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-35202910

RESUMEN

To date, the underlying mechanisms involved intervertebral disc degeneration (IDD) remain unclear, which has hindered the development of molecular biological therapy for IDD. Autophagy is vital for intracellular quality control and metabolic balance in intervertebral disc cells. Hence, autophagy homeostasis is important. Emerging evidence has implicated vitamin D (VD) and the vitamin D receptor (VDR) in IDD progression because of their effects on different autophagy steps. However, the results of clinical trials in which VD supplementation was assessed as a treatment for IDD are controversial. Furthermore, experimental studies on the interplay between VD/VDR and autophagy are still in their infancy. In view of the significance of the crosstalk between VD/VDR and autophagy components, this review focuses on the latest research on VD/VDR modulation in autophagy and investigates the possible regulatory mechanisms. This article will deepen our understanding of the relationship between VD/VDR and autophagy and suggests novel strategies for IDD prevention and treatment.


Asunto(s)
Autofagia , Degeneración del Disco Intervertebral/metabolismo , Receptores de Calcitriol/metabolismo , Deficiencia de Vitamina D/metabolismo , Vitamina D/metabolismo , Humanos , Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/prevención & control , Degeneración del Disco Intervertebral/terapia , Ensayos Clínicos Controlados Aleatorios como Asunto , Vitaminas/metabolismo
19.
Orthop Surg ; 14(3): 463-471, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-35142050

RESUMEN

Intervertebral disc degeneration (IDD) disease has been considered as the main cause of low back pain (LBP), which is a very common symptom and the leading cause of disability worldwide today. The pathological mechanism of IDD remains quite complicated, and genetic, developmental, biochemical, and biomechanical factors all contribute to the development of the disease. There exists no effective, non-surgical treatment for IDD nowadays, which is largely related to the lack of knowledge of the specific mechanisms of IDD, and the lack of effective specific targets. Recently, non-coding RNA, including miRNA, has been recognized as an important regulator of gene expression. Current studies on the effects of miRNA in IDD have confirmed that a variety of miRNAs play a crucial role in the process of IDD via nucleus pulposus cells (NPC) apoptosis, abnormal proliferation, inflammatory factors, the extracellular matrix (ECM) degradation, and annulus fibrosus (AF) degeneration. In the past 10 years, research on miRNA has been quite active in IDD. This review summarizes the current research progression of miRNA in the IDD and puts forward some prospects and challenges on non-surgical treatment for IDD.


Asunto(s)
Degeneración del Disco Intervertebral , Disco Intervertebral , Dolor de la Región Lumbar , MicroARNs , Núcleo Pulposo , Apoptosis , Humanos , Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/genética , Degeneración del Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/terapia , MicroARNs/genética , MicroARNs/metabolismo , Núcleo Pulposo/metabolismo
20.
Int J Mol Sci ; 23(1)2022 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-35008997

RESUMEN

Vertebral disc degenerative disease (DDD) affects millions of people worldwide and is a critical factor leading to low back and neck pain and consequent disability. Currently, no strategy has addressed curing DDD from fundamental aspects, because the pathological mechanism leading to DDD is still controversial. One possible mechanism points to the homeostatic status of extracellular matrix (ECM) anabolism, and catabolism in the disc may play a vital role in the disease's progression. If the damaged disc receives an abundant amount of cartilage, anabolic factors may stimulate the residual cells in the damaged disc to secrete the ECM and mitigate the degeneration process. To examine this hypothesis, a cartilage anabolic factor, Runx1, was expressed by mRNA through a sophisticated polyamine-based PEG-polyplex nanomicelle delivery system in the damaged disc in a rat model. The mRNA medicine and polyamine carrier have favorable safety characteristics and biocompatibility for regenerative medicine. The endocytosis of mRNA-loaded polyplex nanomicelles in vitro, mRNA delivery efficacy, hydration content, disc shrinkage, and ECM in the disc in vivo were also examined. The data revealed that the mRNA-loaded polyplex nanomicelle was promptly engulfed by cellular late endosome, then spread into the cytosol homogeneously at a rate of less than 20 min post-administration of the mRNA medicine. The mRNA expression persisted for at least 6-days post-injection in vivo. Furthermore, the Runx1 mRNA delivered by polyplex nanomicelles increased hydration content by ≈43% in the punctured disc at 4-weeks post-injection (wpi) compared with naked Runx1 mRNA administration. Meanwhile, the disc space and ECM production were also significantly ameliorated in the polyplex nanomicelle group. This study demonstrated that anabolic factor administration by polyplex nanomicelle-protected mRNA medicine, such as Runx1, plays a key role in alleviating the progress of DDD, which is an imbalance scenario of disc metabolism. This platform could be further developed as a promising strategy applied to regenerative medicine.


Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Técnicas de Transferencia de Gen , Degeneración del Disco Intervertebral/genética , Degeneración del Disco Intervertebral/terapia , Micelas , ARN Mensajero/administración & dosificación , Animales , Modelos Animales de Enfermedad , Endocitosis , Expresión Génica , Terapia Genética , Disco Intervertebral/diagnóstico por imagen , Disco Intervertebral/metabolismo , Disco Intervertebral/patología , Degeneración del Disco Intervertebral/diagnóstico por imagen , Degeneración del Disco Intervertebral/patología , Masculino , Imagen Molecular , Nanomedicina , Ratas , Transgenes , Resultado del Tratamiento , Microtomografía por Rayos X
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