Chronic spinal cord compression(CSCC)is induced by disc herniation and other reasons,leading to movement and sensation dysfunction,with a serious impact on quality of life.Spontaneous disc herniation rarely occurs in ...Chronic spinal cord compression(CSCC)is induced by disc herniation and other reasons,leading to movement and sensation dysfunction,with a serious impact on quality of life.Spontaneous disc herniation rarely occurs in rodents,and therefore establishing a chronic spinal cord compression(CSCC)animal model is of crucial importance to explore the pathogenesis and treatment of CSCC.The absence of secreted protein,acidic,and rich in cysteine(SPARC)leads to spontaneous intervertebral disc degeneration in mice,which resembles human disc degeneration.In this study,we evaluated whether SPARC-null mice may serve as an animal model for CSCC.We performed rod rotation test,pain threshold test,gait analysis,and Basso Mouse Scale score.Our results showed that the motor function of SPARC-null mice was weakened,and magnetic resonance images revealed compression at different spinal cord levels,particularly in the lumbar segments.Immunofluorescence staining and western blot assay showed that the absence of SPARC induced apoptosis of neurons and oligodendrocytes,activation of microglia/macrophages with M1/M2 phenotype and astrocytes with A1/A2 phenotype;it also activated the expression of the NOD-like receptor protein 3 inflammasome and inhibited brain-derived neurotrophic factor/tyrosine kinase B signaling pathway.Notably,these findings are characteristics of CSCC.Therefore,we propose that SPARC-null mice may be an animal model for studying CSCC caused by disc herniation.展开更多
BACKGROUND Testicular pain caused by lumbar disease is uncommon in the clinic.Here we reported a case of discogenic low back pain with testicular pain that was successfully cured.CASE SUMMARY A 23-year-old male patien...BACKGROUND Testicular pain caused by lumbar disease is uncommon in the clinic.Here we reported a case of discogenic low back pain with testicular pain that was successfully cured.CASE SUMMARY A 23-year-old male patient presented to our department with chronic low back pain.Based on his clinical symptoms,signs and imaging,he was diagnosed with discogenic low back pain.Since conservative treatment for more than half a year did not significantly improve his low back pain,we decided to treat it with intradiscal methylene blue injection.During the course of surgery,we again identified the low back pain as originating from the degenerated lumbar disc by analgesic discography.Interestingly,the patient’s low back pain disappeared along with the testicular pain that had been present for more than 3 mo.After the operation,the patient’s low back pain improved,and the testicular pain did not reappear.CONCLUSION Intradiscal methylene blue injection is a convenient and effective surgical intervention for the treatment of discogenic low back pain.Lumbar disc degeneration may also be a possible clinical cause of testicular pain.Methylene blue injection in the diseased disc improved the low back pain,and the accom-panying testicular pain was successfully managed.展开更多
Intervertebral disc(ID)degeneration(IDD)is one of the main causes of chronic low back pain,and degenerative lesions are usually caused by an imbalance between catabolic and anabolic processes in the ID.The environment...Intervertebral disc(ID)degeneration(IDD)is one of the main causes of chronic low back pain,and degenerative lesions are usually caused by an imbalance between catabolic and anabolic processes in the ID.The environment in which the ID is located is harsh,with almost no vascular distribution within the disc,and the nutrient supply relies mainly on the diffusion of oxygen and nutrients from the blood vessels located under the endplate.The stability of its internal environment also plays an important role in preventing IDD.The main feature of disc degeneration is a decrease in the number of cells.Mesenchymal stem cells have been used in the treatment of disc lesions due to their ability to differentiate into nucleus pulposus cells in a nonspecific anti-inflammatory manner.The main purpose is to promote their regeneration.The current aim of stem cell therapy is to replace the aged and metamorphosed cells in the ID and to increase the content of the extracellular matrix.The treatment of disc degeneration with stem cells has achieved good efficacy,and the current challenge is how to improve this efficacy.Here,we reviewed current treatments for disc degeneration and summarize studies on stem cell vesicles,enhancement of therapeutic effects when stem cells are mixed with related substances,and improvements in the efficacy of stem cell therapy by adjuvants under adverse conditions.We reviewed the new approaches and ideas for stem cell treatment of disc degeneration in order to contribute to the development of new therapeutic approaches to meet current challenges.展开更多
Karacoline is a compound found in the plant Aconitum kusnezoffii Reichb.Although Aconitum kusnezoffii Reichb is widely used for the treatment of pain,very few studies have been carried out on the use of karacoline due...Karacoline is a compound found in the plant Aconitum kusnezoffii Reichb.Although Aconitum kusnezoffii Reichb is widely used for the treatment of pain,very few studies have been carried out on the use of karacoline due to its potential toxicity.In this study,we selected key matrix metalloproteinases(MMPs),collagen II,and aggrecan as targets due to their association with intervertebral disc degeneration(IDD).Using these targets,we then used network pharmacology to predict a series of molecules that might exert therapeutic effects on IDD.Of these molecules,karacoline was predicted to have the best effect.Tumor necrosis factor(TNF)-a is known to promote the degeneration of the extracellular matrix in IDD.We therefore applied different concentrations of karacoline(0,1.25,or 12.88 mM)along with 100 ng/mL TNF-a to rat nucleus pulposus cells and found that karacoline reduced the expression of MMP-14 in IDD by inhibiting the nuclear factor(NF)-κB pathway,while collagen II and aggrecan expression was increased.This suggested that extracellular matrix degradation was inhibited by karacoline(P<0.05).Our data therefore reveal a new clinical application of karacoline and provide support for the use of network pharmacology in predicting novel drugs.展开更多
Intervertebral disc(IVD)degenerative diseases are a common problem in the world,and they cause substantial social and economic burdens for people.The current methods for treating IVD degenerative diseases mainly inclu...Intervertebral disc(IVD)degenerative diseases are a common problem in the world,and they cause substantial social and economic burdens for people.The current methods for treating IVD degenerative diseases mainly include surgery and conservative treatment,which cannot fundamentally restore the normal structure of the disc.With continuous research on the mechanism of degeneration and the development of regenerative medicine,rapid progress has been made in the field of regenerative medicine regarding the use of stem cell-derived exosomes,which are active biological substances used in intercellular communication,because they show a strong effect in promoting tissue regeneration.The study of exosomes in the field of IVD degeneration has just begun,and many surprising achievements have been made.This paper mainly reviews the biological characteristics of exosomes and highlights the current status of exosomes in the field of IVD degeneration,as well as future developments regarding exosomes.展开更多
ObjectiveTo investigate the gene expression changes in normal and degeneration lumbar intervertebral disc in humans, providing information for clinical. MethodsThe PCR products of 4096 human genes were spotted onto a ...ObjectiveTo investigate the gene expression changes in normal and degeneration lumbar intervertebral disc in humans, providing information for clinical. MethodsThe PCR products of 4096 human genes were spotted onto a kind of chemical-material-coated-glass slides. The total RNAs were isolated from the tissues. Both the mRNAs from the degeneration and normal lumbar intervertebral disc in humans were reversely transcribed to the cDNAs, which used as the hybridization probes with the incorporations of fluorescent dUTP. The mixed probes were then hybridized to the cDNA microarray. After high-stringent washing, the cDNA microarray was scanned for the fluorescent signals and analyzed with computer image analysis. ResultsAmong the 4096 targets, there were 706 genes whose expression levels differed between the degeneration and normal lumbar intervertebral disc in all cases, comprising 298 up-regulated and 358 down-regulated ones. ConclusionDNA microarray technology is an effective technique in screening for differently expressed genes between the degeneration and normal lumbar intervertebral disc. Cell apoptosis plays an important role in the process of lumbar intervertebral disc degeneration.展开更多
Clinical studies have found that patients withcervical degenerative disease are usually accompanied by dizziness.Anterior cervical surgery can eliminate not only chronic neck pain,cervical radiculopathy or myelopathy,...Clinical studies have found that patients withcervical degenerative disease are usually accompanied by dizziness.Anterior cervical surgery can eliminate not only chronic neck pain,cervical radiculopathy or myelopathy,but also dizziness.Immunohistochemical studies show that a large number of mechanoreceptors,especially Ruffini corpuscles,are present in degenerated cervical discs.The available evidence suggests a key role of Ruffini corpuscles in the pathogenesis of dizziness caused by cervical degenerative disease(i.e.cervical discogenic dizziness).Disc degeneration is characterized by an elevation of inflammatory cytokines,which stimulates the mechanoreceptors in degenerated discs and results in peripheral sensitization.Abnormal cervical proprioceptive inputs from the mechanoreceptors are transmitted to the central nervous system,resulting in sensory mismatches with vestibular and visual information and leads to dizziness.In addition,neck pain caused by cervical disc degeneration can play a key role in cervical discogenic dizziness by increasing the sensitivity of muscle spindles.Like cervical discogenic pain,the diagnosis of cervical discogenic dizziness can be challenging and can be made only after other potential causes of dizziness have been ruled out.Conservative treatment is effective for the majority of patients.Existing basic and clinical studies have shown that cervical intervertebral disc degeneration can lead to dizziness.展开更多
Background:A new rat tail intervertebral disc degeneration model was established to observe the morphologic and biologic changes of static bending and compression applied to the discs.Methods:In total,20 Sprague-Dawle...Background:A new rat tail intervertebral disc degeneration model was established to observe the morphologic and biologic changes of static bending and compression applied to the discs.Methods:In total,20 Sprague-Dawley rats with similar weight were randomly di-vided into 4 groups.Group 1 served as a control group for a baseline assessment of normal discs.Group 2 underwent a sham surgery,using an external device to bend the vertebrae of coccygeal 8-10.Groups 3 and 4 were the loaded groups,and exter-nal devices were instrumented to bend the spine with a compression level of 1.8 N and 4.5 N,respectively.Magnetic resonance imaging(MRI),histological,and quanti-tative real-time PCR(qRT-PCR)analysis were performed on all animals on day 14 of the experiment.Results:Magnetic resonance imaging and histological results showed that the changes of intervertebral disc degeneration increased with the size of compression load.Some architecture disorganizations in nucleus pulposus and annulus fibro-sus were found on both of the convex and concave side in the groups of 1.8 N and 4.5 N.An upregulation of MM-3,MM-13,and collagen 1-α1 mRNA expression and a downregulation of collagen 2-α1 and aggrecan mRNA expression were observed in the sham and loading groups.Significant changes were found between the loading groups,whereas the sham group showed similar results to the control group.Conclusions:Static bending and compression could induce progressive disc degen-eration,which could be used for biologic study on disc degeneration promoted by static complex loading.展开更多
BACKGROUND Intervertebral disc degeneration(IVDD)is the leading cause of lower back pain.Disc degeneration is characterized by reduced cellularity and decreased production of extracellular matrix(ECM).Mesenchymal stem...BACKGROUND Intervertebral disc degeneration(IVDD)is the leading cause of lower back pain.Disc degeneration is characterized by reduced cellularity and decreased production of extracellular matrix(ECM).Mesenchymal stem cells(MSCs)have been envisioned as a promising treatment for degenerative illnesses.Cell-based therapy using ECM-producing chondrogenic derivatives of MSCs has the potential to restore the functionality of the intervertebral disc(IVD).AIM To investigate the potential of chondrogenic transcription factors to promote differentiation of human umbilical cord MSCs into chondrocytes,and to assess their therapeutic potential in IVD regeneration.METHODS MSCs were isolated and characterized morphologically and immunologically by the expression of specific markers.MSCs were then transfected with Sox-9 and Six-1 transcription factors to direct differentiation and were assessed for chondrogenic lineage based on the expression of specific markers.These differentiated MSCs were implanted in the rat model of IVDD.The regenerative potential of transplanted cells was investigated using histochemical and molecular analyses of IVDs.RESULTS Isolated cells showed fibroblast-like morphology and expressed CD105,CD90,CD73,CD29,and Vimentin but not CD45 antigens.Overexpression of Sox-9 and Six-1 greatly enhanced the gene expression of transforming growth factor beta-1 gene,BMP,Sox-9,Six-1,and Aggrecan,and protein expression of Sox-9 and Six-1.The implanted cells integrated,survived,and homed in the degenerated intervertebral disc.Histological grading showed that the transfected MSCs regenerated the IVD and restored normal architecture.CONCLUSION Genetically modified MSCs accelerate cartilage regeneration,providing a unique opportunity and impetus for stem cell-based therapeutic approach for degenerative disc diseases.展开更多
BACKGROUND Conventional plain X-ray images of rats,the most common animals used as degeneration models,exhibit unclear vertebral structure and blurry intervertebral disc spaces due to their small size,slender vertebra...BACKGROUND Conventional plain X-ray images of rats,the most common animals used as degeneration models,exhibit unclear vertebral structure and blurry intervertebral disc spaces due to their small size,slender vertebral bodies.AIM To apply molybdenum target X-ray photography in the evaluation of caudal intervertebral disc(IVD)degeneration in rat models.METHODS Two types of rat caudal IVD degeneration models(needle-punctured model and endplate-destructed model)were established,and their effectiveness was verified using nuclear magnetic resonance imaging.Molybdenum target inspection and routine plain X-ray were then performed on these models.Additionally,four observers were assigned to measure the intervertebral height of degenerated segments on molybdenum target plain X-ray images and routine plain X-ray images,respectively.The degeneration was evaluated and statistical analysis was subsequently conducted.RESULTS Nine rats in the needle-punctured model and 10 rats in the endplate-destructed model were effective.Compared with routine plain X-ray images,molybdenum target plain X-ray images showed higher clarity,stronger contrast,as well as clearer and more accurate structural development.The McNemar test confirmed that the difference was statistically significant(P=0.031).In the two models,the reliability of the intervertebral height measured by the four observers on routine plain X-ray images was poor(ICC<0.4),while the data obtained from the molybdenum target plain X-ray images were more reliable.CONCLUSIONMolybdenum target inspection can obtain clearer images and display fine calcification in the imaging evaluation of caudal IVD degeneration in rats,thus ensuring a more accurate evaluation of degeneration.展开更多
<strong>Objective:</strong> To characterize the association between DNA damage and Intervertebral disc degeneration (IDD). <strong>Summary of</strong> <strong>Background Data:</strong&...<strong>Objective:</strong> To characterize the association between DNA damage and Intervertebral disc degeneration (IDD). <strong>Summary of</strong> <strong>Background Data:</strong> IDD is the main disorder causing low back pain and is the most promising target for intervention. Many factors can contribute to the etiology, such as genetics, environment and lifestyle, but it is not yet fully understood. DNA damage can influence this process and needs to be studied, as well as the agents that can determine these damages. <strong>Methods:</strong> A systematic literature search of PubMed, Web of Science and Scopus was performed to identify studies related to DNA damage to the intervertebral disc. <strong>Results:</strong> After screening 61 records, 7 articles were included according to the selection criteria. All studies showed some relation between DNA damage and IDD. However, DNA damage was always considered a secondary issue to be investigated. <strong>Conclusions:</strong> Many factors can influence DNA damage induced by different genotoxic agents on the degenerative cascade of IVD. However, the correlation between IDD severity and DNA damage, as well as the factual role of DNA damage in disc degeneration could not be defined.展开更多
Degenerative disc disease is the most common cause of low back pain. Intervertebral disc abnormalities are commonly evaluated by magnetic resonance imaging (MRI), and Pfirrmann’s system involves the use of T2-weighte...Degenerative disc disease is the most common cause of low back pain. Intervertebral disc abnormalities are commonly evaluated by magnetic resonance imaging (MRI), and Pfirrmann’s system involves the use of T2-weighted images (T2WI) to classify disc degeneration. However, as this classification is based on visual evaluation, it is not possible to quantify degeneration using this method. The present study was performed to establish an MRI-based intervertebral disc classification system using diffusional kurtosis imaging (DKI), to quantify intervertebral disc water content according to the Pfirrmann classification. Sagittal mean diffusional kurtosis (MK) mapping was performed for the L3/4, L4/5, and L5/S1 intervertebral discs in 32 patients (15 female, 17 male;age range, 24 - 82 years;mean age, 57.7 years). The degree of disc degeneration was assessed in the midsagittal section on T2WI according to the Pfirrmann classification (grade I - V). The relationships between MK values, which are correlated with intervertebral disc composition changes, and grade of degeneration determined using the Pfirrmann classification were analyzed. The MK values tended to decrease with increasing grade of degeneration, and differed significantly between grades I and IV, but not between grade IV and V (P < 0.05, Mann-Whitney U test). DKI is an effective means of detecting the early stages of disc degeneration. Therefore, DKI may be a useful diagnostic tool for quantitative assessment of intervertebral disc degeneration.展开更多
<strong>Objective:</strong> To describe the relationship between autophagy and apoptosis and the possible signaling pathways involved in degenerative lumbar intervertebral disc. <strong>Summary of Ba...<strong>Objective:</strong> To describe the relationship between autophagy and apoptosis and the possible signaling pathways involved in degenerative lumbar intervertebral disc. <strong>Summary of Background Data:</strong> Autophagy and apoptosis are regulatory cellular mechanisms that determine many pathologies, including degenerative intervertebral disc disease. The interactions between these events in the damage or protection of intervertebral disc cells and in cellular homeostasis remain controversial. <strong>Methods:</strong> The sample size was twenty patients who underwent lumbar spine surgery for symptomatic disc herniation or spondylolisthesis. Intervertebral discs were classified by magnetic resonance as Pfirrmann grade IV and grade V. Six patients were operated on two levels, resulting in twenty-six intervertebral discs that were submitted to immunohistochemistry to verify the protein expression of autophagy and apoptosis markers. <strong>Results: </strong>The autophagic markers had greater protein expression in the human intervertebral disc (Pfirrmann Grades IV and V). Under these conditions, autophagy and apoptosis showed a negative correlation. Regarding apoptosis, caspase 8 presented the highest protein expression, which allows inferring the preference for the extrinsic pathway in cell death. <strong>Conclusions: </strong>Autophagy had the greatest protein expression negative profile compared to apoptosis. Caspase 8 had the highest protein expression in apoptosis.展开更多
The lumbar spine,an important part of the body’s motor mechanism,is more susceptible to damage as it bears most of the body’s load.Age can cause clinical manifestations such as neurological impairment,back and leg p...The lumbar spine,an important part of the body’s motor mechanism,is more susceptible to damage as it bears most of the body’s load.Age can cause clinical manifestations such as neurological impairment,back and leg pain in the lumbar spine.External forces result in nucleus pulposus out,destruction of the intervertebral disc fibrous ring,and gradual aging and damage.Lumbar degenerative change is a common middle-aged and old-aged disease,and its clinical symptoms on the initial stage are not obvious,but it becomes more and more serious as they get older.Patients with severe lumbar degenerative changes will appear symptoms such as urinary and fecal incontinence,lower extremity numbness,back pain,and sexual dysfunction.The main reason for back pain and leg pain is the degenerative changes in the lumbar intervertebral discs,at the same time which also leads to patients’lumbar instability.This study focuses on the correlation analysis of intervertebral disc degeneration with HTRA1 and HAPLN1 gene polymorphisms.展开更多
Due to the ethical concern and inability to detect inner stress distributions of intervertebral disc(IVD),traditional methods for investigation of intervertebral disc degeneration(IVDD)have significant limitations.Man...Due to the ethical concern and inability to detect inner stress distributions of intervertebral disc(IVD),traditional methods for investigation of intervertebral disc degeneration(IVDD)have significant limitations.Many researchers have demonstrated that finite element analysis(FEA)is an effective tool for the research of IVDD.However,the specific application of FEA for investigation of IVDD has not been systematically elucidated before.In the present review,we summarize the current finite element models(FEM)used for the investigation of IVDD,including the poroelastic non linear FEM,difTusive-reactive theory model and cell-activity coupled mechano-electrochemical theory model.We further elaborate the use of FEA for the research of IVDD pathogenesis especially for nutrition and biomechanics associated etiology,and the biological,biomechanical and clinical influences of IVDD.In addition,the application of FEA for evaluation and exploration of various treatments for IVDD is also elucidated.We conclude that FEA is an excellent technique for research of IVDD,which could be used to explore the etiology,biology and biomechanics of IVDD.In the future,FEA may help us to achieve the goal of individualized precision therapy.展开更多
Objective:To investigate the effect of osteoporosis and intervertebral disc degeneration on the endplate cartilage injury in rats.Methods:A total of 48 female Sprague Dawley rats(3 months)were randomly divided into Gr...Objective:To investigate the effect of osteoporosis and intervertebral disc degeneration on the endplate cartilage injury in rats.Methods:A total of 48 female Sprague Dawley rats(3 months)were randomly divided into Groups A,B,C and D with 12 rats in each group.Osteoporosis and intervertebral disc degeneration composite model,simple degeneration model and simple osteoporosis model were prepared in Groups A,B and C respectively.After modeling,four rats of each group at 12th.18th and 24th week were sacrificed,Intervertebral height of cervical vertebra C6/C7 was measured.Micro-CT was used to image the endplate of cephalic and caudal cartilage at C6/C7 intervertebral disc.Abraded area rate of C6 caudal and C7 cephalic cartilage endplate was calculated,and then C6/C7 intervertebral disc was routinely embedded and sectioned.stained with safranin O to observe histological changes microscopically.Results:At 12,18 and24 weeks,intervertebral disc height of C6/C7 were(0.58±0.09)mm,(0.53±0.04)mm and(0.04±0.06)mm in Group A rats,(0.55±0.05)mm,(0.52±0.07)mm and(0.07±0.05)mm in Group B rats.At 24th week.intervertebral disc height of Group A rats was significantly lower than that of Group B rats(P<0.05);intervertebral disc height of Groups A and B rats at each time point were significantly lower than that of Groups C and D(P<0.05).There was no significantly statistical difference of intervertebral disc height between Groups C and D(P>0.05).At 12 and 18 weeks,the abraded rate of C6 caudal and C7 cephalic cartilage endplate in Group A rats were significantly higher than that in Groups B.C and D rats(P<0.05);the abraded rate in Group B was significantly higher than that in Groups C and D(P>0.05).Microscopic observation of CT showed that ventral defects in C6caudal or C7 cephalic cartilage endplate in Groups A and B appeared after 12 weeks of modeling;obvious cracks were found in front of the C6 and C7 vertebral body,and cartilage defect shown the trend of"repairing"at 18 and 24 weeks after modeling.Conclusions:Intervertebral disc degeneration and osteoporosis can cause damage to the cartilage endplate.Co-existence of these two factors can induce more serious damage to the endplate.which has possitive correlation with intervertebral disc degeneration.Osteoporosis plays a certain role in intervertebral disc degeneration process,and accelerates the degeneration of intervertebral disc in a specific time window.展开更多
Low back pain has become more prevalent in recent years,causing enormous economic burden for society and government.Common therapies used in clinics including conservative treatment and surgery can only relieve pain.S...Low back pain has become more prevalent in recent years,causing enormous economic burden for society and government.Common therapies used in clinics including conservative treatment and surgery can only relieve pain.Subsequent cell-based treatment such as mesenchymal stem cell transplantation poses problems such as short duration of therapeutic effect and tumorigenesis.Recently,the discovery and identification of stem cell niche and stem/progenitor cells in intervertebral disc bring increased attention to endogenous repair strategy.Therefore,we review the studies involving endogenous repair strategy and present the characteristics and current status of this treatment.Meanwhile,we also discuss the strategy and perspective of endogenous repair strategy in future.展开更多
Low back pain(LBP),as a leading cause of disability,is a common musculoskeletal disorder that results in major social and economic burdens.Recent research has identified inflammation and related signaling pathways as ...Low back pain(LBP),as a leading cause of disability,is a common musculoskeletal disorder that results in major social and economic burdens.Recent research has identified inflammation and related signaling pathways as important factors in the onset and progression of disc degeneration,a significant contributor to LBP.Inflammatory mediators also play an indispensable role in discogenic LBP.The suppression of LBP is a primary goal of clinical practice but has not received enough attention in disc research studies.Here,an overview of the advances in inflammation-related pain in disc degeneration is provided,with a discussion on the role of inflammation in IVD degeneration and pain induction.Puncture models,mechanical models,and spontaneous models as the main animal models to study painful disc degeneration are discussed,and the underlying signaling pathways are summarized.Furthermore,potential drug candidates,either under laboratory investigation or undergoing clinical trials,to suppress discogenic LBP by eliminating inflammation are explored.We hope to attract more research interest to address inflammation and pain in IDD and contribute to promoting more translational research.展开更多
The inflammatory response is induced by the overexpression of inflammatory cytokines, mainly interleukin(IL)-1β, and is one of the main causes of intervertebral disc degeneration(IVDD). NLR pyrin domain containing 3(...The inflammatory response is induced by the overexpression of inflammatory cytokines, mainly interleukin(IL)-1β, and is one of the main causes of intervertebral disc degeneration(IVDD). NLR pyrin domain containing 3(NLRP3) inflammasome activation is an important source of IL-1β. As an anti-inflammatory neuroendocrine hormone, melatonin plays various roles in different pathophysiological conditions. However, its roles in IVDD are still not well understood and require more examination. First, we demonstrated that melatonin delayed the progression of IVDD and relieved IVDD-related low back pain in a rat needle puncture IVDD model;moreover, NLRP3 inflammasome activation(NLRP3, p20, and IL-1β levels) was significantly upregulated in severely degenerated human discs and a rat IVDD model. Subsequently, an IL-1β/NF-κB-NLRP3 inflammasome activation positive feedback loop was found in nucleus pulposus(NP) cells that were treated with IL-1β. In these cells, expression of NLRP3 and p20 was significantly increased, NF-κB signaling was involved in this regulation, and mitochondrial reactive oxygen species(mt ROS)production increased. Furthermore, we found that melatonin disrupted the IL-1β/NF-κB-NLRP3 inflammasome activation positive feedback loop in vitro and in vivo. Melatonin treatment decreased NLRP3, p20, and IL-1β levels by inhibiting NF-κB signaling and downregulating mt ROS production. Finally, we showed that melatonin mediated the disruption of the positive feedback loop of IL-1β in vivo. In this study, we showed for the first time that IL-1β promotes its own expression by upregulating NLRP3 inflammasome activation. Furthermore, melatonin disrupts the IL-1β positive feedback loop and may be a potential therapeutic agent for IVDD.展开更多
Lower back pain is a leading cause of disability and is one of the reasons for the substantial socioeconomic burden.The etiology of intervertebral disc(IVD)degeneration is complicated,and its mechanism is still not co...Lower back pain is a leading cause of disability and is one of the reasons for the substantial socioeconomic burden.The etiology of intervertebral disc(IVD)degeneration is complicated,and its mechanism is still not completely understood.Factors such as aging,systemic inflammation,biochemical mediators,toxic environmental factors,physical injuries,and genetic factors are involved in the progression of its pathophysiology.Currently,no therapy for restoring degenerated IVD is available except pain management,reduced physical activities,and surgical intervention.Therefore,it is imperative to establish regenerative medicine-based approaches to heal and repair the injured disc,repopulate the cell types to retain water content,synthesize extracellular matrix,and strengthen the disc to restore normal spine flexion.Cellular therapy has gained attention for IVD management as an alternative therapeutic option.In this review,we present an overview of the anatomical and molecular structure and the surrounding pathophysiology of the IVD.Modern therapeutic approaches,including proteins and growth factors,cellular and gene therapy,and cell fate regulators are reviewed.Similarly,small molecules that modulate the fate of stem cells for their differentiation into chondrocytes and notochordal cell types are highlighted.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82074454(to XJC),82174409(to MY),81930116(to YJW),81873317(to XJC)the National Key R&D Program of China,No.2018YFC1704300(to YJW)the Natural Science Foundation of Shanghai,No.20ZR1459000(to MY)。
文摘Chronic spinal cord compression(CSCC)is induced by disc herniation and other reasons,leading to movement and sensation dysfunction,with a serious impact on quality of life.Spontaneous disc herniation rarely occurs in rodents,and therefore establishing a chronic spinal cord compression(CSCC)animal model is of crucial importance to explore the pathogenesis and treatment of CSCC.The absence of secreted protein,acidic,and rich in cysteine(SPARC)leads to spontaneous intervertebral disc degeneration in mice,which resembles human disc degeneration.In this study,we evaluated whether SPARC-null mice may serve as an animal model for CSCC.We performed rod rotation test,pain threshold test,gait analysis,and Basso Mouse Scale score.Our results showed that the motor function of SPARC-null mice was weakened,and magnetic resonance images revealed compression at different spinal cord levels,particularly in the lumbar segments.Immunofluorescence staining and western blot assay showed that the absence of SPARC induced apoptosis of neurons and oligodendrocytes,activation of microglia/macrophages with M1/M2 phenotype and astrocytes with A1/A2 phenotype;it also activated the expression of the NOD-like receptor protein 3 inflammasome and inhibited brain-derived neurotrophic factor/tyrosine kinase B signaling pathway.Notably,these findings are characteristics of CSCC.Therefore,we propose that SPARC-null mice may be an animal model for studying CSCC caused by disc herniation.
文摘BACKGROUND Testicular pain caused by lumbar disease is uncommon in the clinic.Here we reported a case of discogenic low back pain with testicular pain that was successfully cured.CASE SUMMARY A 23-year-old male patient presented to our department with chronic low back pain.Based on his clinical symptoms,signs and imaging,he was diagnosed with discogenic low back pain.Since conservative treatment for more than half a year did not significantly improve his low back pain,we decided to treat it with intradiscal methylene blue injection.During the course of surgery,we again identified the low back pain as originating from the degenerated lumbar disc by analgesic discography.Interestingly,the patient’s low back pain disappeared along with the testicular pain that had been present for more than 3 mo.After the operation,the patient’s low back pain improved,and the testicular pain did not reappear.CONCLUSION Intradiscal methylene blue injection is a convenient and effective surgical intervention for the treatment of discogenic low back pain.Lumbar disc degeneration may also be a possible clinical cause of testicular pain.Methylene blue injection in the diseased disc improved the low back pain,and the accom-panying testicular pain was successfully managed.
基金National Natural Science Foundation of China,No.82202766Natural Science Foundation of Hubei Province of China,No.2022CFB686+1 种基金Science Foundation of Union Hospital,No.2021xhyn102Scientific Research Training Program for Young Talents in Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,China.
文摘Intervertebral disc(ID)degeneration(IDD)is one of the main causes of chronic low back pain,and degenerative lesions are usually caused by an imbalance between catabolic and anabolic processes in the ID.The environment in which the ID is located is harsh,with almost no vascular distribution within the disc,and the nutrient supply relies mainly on the diffusion of oxygen and nutrients from the blood vessels located under the endplate.The stability of its internal environment also plays an important role in preventing IDD.The main feature of disc degeneration is a decrease in the number of cells.Mesenchymal stem cells have been used in the treatment of disc lesions due to their ability to differentiate into nucleus pulposus cells in a nonspecific anti-inflammatory manner.The main purpose is to promote their regeneration.The current aim of stem cell therapy is to replace the aged and metamorphosed cells in the ID and to increase the content of the extracellular matrix.The treatment of disc degeneration with stem cells has achieved good efficacy,and the current challenge is how to improve this efficacy.Here,we reviewed current treatments for disc degeneration and summarize studies on stem cell vesicles,enhancement of therapeutic effects when stem cells are mixed with related substances,and improvements in the efficacy of stem cell therapy by adjuvants under adverse conditions.We reviewed the new approaches and ideas for stem cell treatment of disc degeneration in order to contribute to the development of new therapeutic approaches to meet current challenges.
文摘Karacoline is a compound found in the plant Aconitum kusnezoffii Reichb.Although Aconitum kusnezoffii Reichb is widely used for the treatment of pain,very few studies have been carried out on the use of karacoline due to its potential toxicity.In this study,we selected key matrix metalloproteinases(MMPs),collagen II,and aggrecan as targets due to their association with intervertebral disc degeneration(IDD).Using these targets,we then used network pharmacology to predict a series of molecules that might exert therapeutic effects on IDD.Of these molecules,karacoline was predicted to have the best effect.Tumor necrosis factor(TNF)-a is known to promote the degeneration of the extracellular matrix in IDD.We therefore applied different concentrations of karacoline(0,1.25,or 12.88 mM)along with 100 ng/mL TNF-a to rat nucleus pulposus cells and found that karacoline reduced the expression of MMP-14 in IDD by inhibiting the nuclear factor(NF)-κB pathway,while collagen II and aggrecan expression was increased.This suggested that extracellular matrix degradation was inhibited by karacoline(P<0.05).Our data therefore reveal a new clinical application of karacoline and provide support for the use of network pharmacology in predicting novel drugs.
文摘Intervertebral disc(IVD)degenerative diseases are a common problem in the world,and they cause substantial social and economic burdens for people.The current methods for treating IVD degenerative diseases mainly include surgery and conservative treatment,which cannot fundamentally restore the normal structure of the disc.With continuous research on the mechanism of degeneration and the development of regenerative medicine,rapid progress has been made in the field of regenerative medicine regarding the use of stem cell-derived exosomes,which are active biological substances used in intercellular communication,because they show a strong effect in promoting tissue regeneration.The study of exosomes in the field of IVD degeneration has just begun,and many surprising achievements have been made.This paper mainly reviews the biological characteristics of exosomes and highlights the current status of exosomes in the field of IVD degeneration,as well as future developments regarding exosomes.
文摘ObjectiveTo investigate the gene expression changes in normal and degeneration lumbar intervertebral disc in humans, providing information for clinical. MethodsThe PCR products of 4096 human genes were spotted onto a kind of chemical-material-coated-glass slides. The total RNAs were isolated from the tissues. Both the mRNAs from the degeneration and normal lumbar intervertebral disc in humans were reversely transcribed to the cDNAs, which used as the hybridization probes with the incorporations of fluorescent dUTP. The mixed probes were then hybridized to the cDNA microarray. After high-stringent washing, the cDNA microarray was scanned for the fluorescent signals and analyzed with computer image analysis. ResultsAmong the 4096 targets, there were 706 genes whose expression levels differed between the degeneration and normal lumbar intervertebral disc in all cases, comprising 298 up-regulated and 358 down-regulated ones. ConclusionDNA microarray technology is an effective technique in screening for differently expressed genes between the degeneration and normal lumbar intervertebral disc. Cell apoptosis plays an important role in the process of lumbar intervertebral disc degeneration.
文摘Clinical studies have found that patients withcervical degenerative disease are usually accompanied by dizziness.Anterior cervical surgery can eliminate not only chronic neck pain,cervical radiculopathy or myelopathy,but also dizziness.Immunohistochemical studies show that a large number of mechanoreceptors,especially Ruffini corpuscles,are present in degenerated cervical discs.The available evidence suggests a key role of Ruffini corpuscles in the pathogenesis of dizziness caused by cervical degenerative disease(i.e.cervical discogenic dizziness).Disc degeneration is characterized by an elevation of inflammatory cytokines,which stimulates the mechanoreceptors in degenerated discs and results in peripheral sensitization.Abnormal cervical proprioceptive inputs from the mechanoreceptors are transmitted to the central nervous system,resulting in sensory mismatches with vestibular and visual information and leads to dizziness.In addition,neck pain caused by cervical disc degeneration can play a key role in cervical discogenic dizziness by increasing the sensitivity of muscle spindles.Like cervical discogenic pain,the diagnosis of cervical discogenic dizziness can be challenging and can be made only after other potential causes of dizziness have been ruled out.Conservative treatment is effective for the majority of patients.Existing basic and clinical studies have shown that cervical intervertebral disc degeneration can lead to dizziness.
文摘Background:A new rat tail intervertebral disc degeneration model was established to observe the morphologic and biologic changes of static bending and compression applied to the discs.Methods:In total,20 Sprague-Dawley rats with similar weight were randomly di-vided into 4 groups.Group 1 served as a control group for a baseline assessment of normal discs.Group 2 underwent a sham surgery,using an external device to bend the vertebrae of coccygeal 8-10.Groups 3 and 4 were the loaded groups,and exter-nal devices were instrumented to bend the spine with a compression level of 1.8 N and 4.5 N,respectively.Magnetic resonance imaging(MRI),histological,and quanti-tative real-time PCR(qRT-PCR)analysis were performed on all animals on day 14 of the experiment.Results:Magnetic resonance imaging and histological results showed that the changes of intervertebral disc degeneration increased with the size of compression load.Some architecture disorganizations in nucleus pulposus and annulus fibro-sus were found on both of the convex and concave side in the groups of 1.8 N and 4.5 N.An upregulation of MM-3,MM-13,and collagen 1-α1 mRNA expression and a downregulation of collagen 2-α1 and aggrecan mRNA expression were observed in the sham and loading groups.Significant changes were found between the loading groups,whereas the sham group showed similar results to the control group.Conclusions:Static bending and compression could induce progressive disc degen-eration,which could be used for biologic study on disc degeneration promoted by static complex loading.
基金Supported by Higher Education Commission Pakistan,No. 7083
文摘BACKGROUND Intervertebral disc degeneration(IVDD)is the leading cause of lower back pain.Disc degeneration is characterized by reduced cellularity and decreased production of extracellular matrix(ECM).Mesenchymal stem cells(MSCs)have been envisioned as a promising treatment for degenerative illnesses.Cell-based therapy using ECM-producing chondrogenic derivatives of MSCs has the potential to restore the functionality of the intervertebral disc(IVD).AIM To investigate the potential of chondrogenic transcription factors to promote differentiation of human umbilical cord MSCs into chondrocytes,and to assess their therapeutic potential in IVD regeneration.METHODS MSCs were isolated and characterized morphologically and immunologically by the expression of specific markers.MSCs were then transfected with Sox-9 and Six-1 transcription factors to direct differentiation and were assessed for chondrogenic lineage based on the expression of specific markers.These differentiated MSCs were implanted in the rat model of IVDD.The regenerative potential of transplanted cells was investigated using histochemical and molecular analyses of IVDs.RESULTS Isolated cells showed fibroblast-like morphology and expressed CD105,CD90,CD73,CD29,and Vimentin but not CD45 antigens.Overexpression of Sox-9 and Six-1 greatly enhanced the gene expression of transforming growth factor beta-1 gene,BMP,Sox-9,Six-1,and Aggrecan,and protein expression of Sox-9 and Six-1.The implanted cells integrated,survived,and homed in the degenerated intervertebral disc.Histological grading showed that the transfected MSCs regenerated the IVD and restored normal architecture.CONCLUSION Genetically modified MSCs accelerate cartilage regeneration,providing a unique opportunity and impetus for stem cell-based therapeutic approach for degenerative disc diseases.
基金Supported by the National Key Research and Development Program of China,No.2017YFA0105404。
文摘BACKGROUND Conventional plain X-ray images of rats,the most common animals used as degeneration models,exhibit unclear vertebral structure and blurry intervertebral disc spaces due to their small size,slender vertebral bodies.AIM To apply molybdenum target X-ray photography in the evaluation of caudal intervertebral disc(IVD)degeneration in rat models.METHODS Two types of rat caudal IVD degeneration models(needle-punctured model and endplate-destructed model)were established,and their effectiveness was verified using nuclear magnetic resonance imaging.Molybdenum target inspection and routine plain X-ray were then performed on these models.Additionally,four observers were assigned to measure the intervertebral height of degenerated segments on molybdenum target plain X-ray images and routine plain X-ray images,respectively.The degeneration was evaluated and statistical analysis was subsequently conducted.RESULTS Nine rats in the needle-punctured model and 10 rats in the endplate-destructed model were effective.Compared with routine plain X-ray images,molybdenum target plain X-ray images showed higher clarity,stronger contrast,as well as clearer and more accurate structural development.The McNemar test confirmed that the difference was statistically significant(P=0.031).In the two models,the reliability of the intervertebral height measured by the four observers on routine plain X-ray images was poor(ICC<0.4),while the data obtained from the molybdenum target plain X-ray images were more reliable.CONCLUSIONMolybdenum target inspection can obtain clearer images and display fine calcification in the imaging evaluation of caudal IVD degeneration in rats,thus ensuring a more accurate evaluation of degeneration.
文摘<strong>Objective:</strong> To characterize the association between DNA damage and Intervertebral disc degeneration (IDD). <strong>Summary of</strong> <strong>Background Data:</strong> IDD is the main disorder causing low back pain and is the most promising target for intervention. Many factors can contribute to the etiology, such as genetics, environment and lifestyle, but it is not yet fully understood. DNA damage can influence this process and needs to be studied, as well as the agents that can determine these damages. <strong>Methods:</strong> A systematic literature search of PubMed, Web of Science and Scopus was performed to identify studies related to DNA damage to the intervertebral disc. <strong>Results:</strong> After screening 61 records, 7 articles were included according to the selection criteria. All studies showed some relation between DNA damage and IDD. However, DNA damage was always considered a secondary issue to be investigated. <strong>Conclusions:</strong> Many factors can influence DNA damage induced by different genotoxic agents on the degenerative cascade of IVD. However, the correlation between IDD severity and DNA damage, as well as the factual role of DNA damage in disc degeneration could not be defined.
文摘Degenerative disc disease is the most common cause of low back pain. Intervertebral disc abnormalities are commonly evaluated by magnetic resonance imaging (MRI), and Pfirrmann’s system involves the use of T2-weighted images (T2WI) to classify disc degeneration. However, as this classification is based on visual evaluation, it is not possible to quantify degeneration using this method. The present study was performed to establish an MRI-based intervertebral disc classification system using diffusional kurtosis imaging (DKI), to quantify intervertebral disc water content according to the Pfirrmann classification. Sagittal mean diffusional kurtosis (MK) mapping was performed for the L3/4, L4/5, and L5/S1 intervertebral discs in 32 patients (15 female, 17 male;age range, 24 - 82 years;mean age, 57.7 years). The degree of disc degeneration was assessed in the midsagittal section on T2WI according to the Pfirrmann classification (grade I - V). The relationships between MK values, which are correlated with intervertebral disc composition changes, and grade of degeneration determined using the Pfirrmann classification were analyzed. The MK values tended to decrease with increasing grade of degeneration, and differed significantly between grades I and IV, but not between grade IV and V (P < 0.05, Mann-Whitney U test). DKI is an effective means of detecting the early stages of disc degeneration. Therefore, DKI may be a useful diagnostic tool for quantitative assessment of intervertebral disc degeneration.
文摘<strong>Objective:</strong> To describe the relationship between autophagy and apoptosis and the possible signaling pathways involved in degenerative lumbar intervertebral disc. <strong>Summary of Background Data:</strong> Autophagy and apoptosis are regulatory cellular mechanisms that determine many pathologies, including degenerative intervertebral disc disease. The interactions between these events in the damage or protection of intervertebral disc cells and in cellular homeostasis remain controversial. <strong>Methods:</strong> The sample size was twenty patients who underwent lumbar spine surgery for symptomatic disc herniation or spondylolisthesis. Intervertebral discs were classified by magnetic resonance as Pfirrmann grade IV and grade V. Six patients were operated on two levels, resulting in twenty-six intervertebral discs that were submitted to immunohistochemistry to verify the protein expression of autophagy and apoptosis markers. <strong>Results: </strong>The autophagic markers had greater protein expression in the human intervertebral disc (Pfirrmann Grades IV and V). Under these conditions, autophagy and apoptosis showed a negative correlation. Regarding apoptosis, caspase 8 presented the highest protein expression, which allows inferring the preference for the extrinsic pathway in cell death. <strong>Conclusions: </strong>Autophagy had the greatest protein expression negative profile compared to apoptosis. Caspase 8 had the highest protein expression in apoptosis.
基金This work was supported by the Project of the Department of Science and Technology in Shaanxi Province(2020JM-702).
文摘The lumbar spine,an important part of the body’s motor mechanism,is more susceptible to damage as it bears most of the body’s load.Age can cause clinical manifestations such as neurological impairment,back and leg pain in the lumbar spine.External forces result in nucleus pulposus out,destruction of the intervertebral disc fibrous ring,and gradual aging and damage.Lumbar degenerative change is a common middle-aged and old-aged disease,and its clinical symptoms on the initial stage are not obvious,but it becomes more and more serious as they get older.Patients with severe lumbar degenerative changes will appear symptoms such as urinary and fecal incontinence,lower extremity numbness,back pain,and sexual dysfunction.The main reason for back pain and leg pain is the degenerative changes in the lumbar intervertebral discs,at the same time which also leads to patients’lumbar instability.This study focuses on the correlation analysis of intervertebral disc degeneration with HTRA1 and HAPLN1 gene polymorphisms.
基金the National Key Research and Development Program of China(No.2016YFC1100100)Major Research Plan of National Natural Science Foundation of China(No.91649204).
文摘Due to the ethical concern and inability to detect inner stress distributions of intervertebral disc(IVD),traditional methods for investigation of intervertebral disc degeneration(IVDD)have significant limitations.Many researchers have demonstrated that finite element analysis(FEA)is an effective tool for the research of IVDD.However,the specific application of FEA for investigation of IVDD has not been systematically elucidated before.In the present review,we summarize the current finite element models(FEM)used for the investigation of IVDD,including the poroelastic non linear FEM,difTusive-reactive theory model and cell-activity coupled mechano-electrochemical theory model.We further elaborate the use of FEA for the research of IVDD pathogenesis especially for nutrition and biomechanics associated etiology,and the biological,biomechanical and clinical influences of IVDD.In addition,the application of FEA for evaluation and exploration of various treatments for IVDD is also elucidated.We conclude that FEA is an excellent technique for research of IVDD,which could be used to explore the etiology,biology and biomechanics of IVDD.In the future,FEA may help us to achieve the goal of individualized precision therapy.
基金supported by National Science Foundation.Grant No.81171764
文摘Objective:To investigate the effect of osteoporosis and intervertebral disc degeneration on the endplate cartilage injury in rats.Methods:A total of 48 female Sprague Dawley rats(3 months)were randomly divided into Groups A,B,C and D with 12 rats in each group.Osteoporosis and intervertebral disc degeneration composite model,simple degeneration model and simple osteoporosis model were prepared in Groups A,B and C respectively.After modeling,four rats of each group at 12th.18th and 24th week were sacrificed,Intervertebral height of cervical vertebra C6/C7 was measured.Micro-CT was used to image the endplate of cephalic and caudal cartilage at C6/C7 intervertebral disc.Abraded area rate of C6 caudal and C7 cephalic cartilage endplate was calculated,and then C6/C7 intervertebral disc was routinely embedded and sectioned.stained with safranin O to observe histological changes microscopically.Results:At 12,18 and24 weeks,intervertebral disc height of C6/C7 were(0.58±0.09)mm,(0.53±0.04)mm and(0.04±0.06)mm in Group A rats,(0.55±0.05)mm,(0.52±0.07)mm and(0.07±0.05)mm in Group B rats.At 24th week.intervertebral disc height of Group A rats was significantly lower than that of Group B rats(P<0.05);intervertebral disc height of Groups A and B rats at each time point were significantly lower than that of Groups C and D(P<0.05).There was no significantly statistical difference of intervertebral disc height between Groups C and D(P>0.05).At 12 and 18 weeks,the abraded rate of C6 caudal and C7 cephalic cartilage endplate in Group A rats were significantly higher than that in Groups B.C and D rats(P<0.05);the abraded rate in Group B was significantly higher than that in Groups C and D(P>0.05).Microscopic observation of CT showed that ventral defects in C6caudal or C7 cephalic cartilage endplate in Groups A and B appeared after 12 weeks of modeling;obvious cracks were found in front of the C6 and C7 vertebral body,and cartilage defect shown the trend of"repairing"at 18 and 24 weeks after modeling.Conclusions:Intervertebral disc degeneration and osteoporosis can cause damage to the cartilage endplate.Co-existence of these two factors can induce more serious damage to the endplate.which has possitive correlation with intervertebral disc degeneration.Osteoporosis plays a certain role in intervertebral disc degeneration process,and accelerates the degeneration of intervertebral disc in a specific time window.
基金National Natural Science Foundation of China,No.81972136National Natural Science Foundation for Young Scholars of China,No.81401830+3 种基金Guangxi Natural Science Foundation General Project,No.2018JJA14775Young Medical Scholars Major Program of Jiangsu Province,No.QNRC2016342Innovation Team Project of Jiangsu Province,No.CXTDB2017004Key Funding Project of Maternal and Child Health Research of Jiangsu Province,No.F201801.
文摘Low back pain has become more prevalent in recent years,causing enormous economic burden for society and government.Common therapies used in clinics including conservative treatment and surgery can only relieve pain.Subsequent cell-based treatment such as mesenchymal stem cell transplantation poses problems such as short duration of therapeutic effect and tumorigenesis.Recently,the discovery and identification of stem cell niche and stem/progenitor cells in intervertebral disc bring increased attention to endogenous repair strategy.Therefore,we review the studies involving endogenous repair strategy and present the characteristics and current status of this treatment.Meanwhile,we also discuss the strategy and perspective of endogenous repair strategy in future.
基金the National Natural Science Foundation of China(81772386,81702191,81572175,81371984,and 81071511)the Guangdong-Hong Kong Joint Innovation Project of Guangdong Province(2017A050506019)the Natural Science Foundation of Guangdong Province,China(2020A1515011031).
文摘Low back pain(LBP),as a leading cause of disability,is a common musculoskeletal disorder that results in major social and economic burdens.Recent research has identified inflammation and related signaling pathways as important factors in the onset and progression of disc degeneration,a significant contributor to LBP.Inflammatory mediators also play an indispensable role in discogenic LBP.The suppression of LBP is a primary goal of clinical practice but has not received enough attention in disc research studies.Here,an overview of the advances in inflammation-related pain in disc degeneration is provided,with a discussion on the role of inflammation in IVD degeneration and pain induction.Puncture models,mechanical models,and spontaneous models as the main animal models to study painful disc degeneration are discussed,and the underlying signaling pathways are summarized.Furthermore,potential drug candidates,either under laboratory investigation or undergoing clinical trials,to suppress discogenic LBP by eliminating inflammation are explored.We hope to attract more research interest to address inflammation and pain in IDD and contribute to promoting more translational research.
基金supported by grants from the Natural Science Foundation of Guangdong Province (Grant no: 2017A030313670)the National Natural Science Foundation of China (81572175 and 81772386)。
文摘The inflammatory response is induced by the overexpression of inflammatory cytokines, mainly interleukin(IL)-1β, and is one of the main causes of intervertebral disc degeneration(IVDD). NLR pyrin domain containing 3(NLRP3) inflammasome activation is an important source of IL-1β. As an anti-inflammatory neuroendocrine hormone, melatonin plays various roles in different pathophysiological conditions. However, its roles in IVDD are still not well understood and require more examination. First, we demonstrated that melatonin delayed the progression of IVDD and relieved IVDD-related low back pain in a rat needle puncture IVDD model;moreover, NLRP3 inflammasome activation(NLRP3, p20, and IL-1β levels) was significantly upregulated in severely degenerated human discs and a rat IVDD model. Subsequently, an IL-1β/NF-κB-NLRP3 inflammasome activation positive feedback loop was found in nucleus pulposus(NP) cells that were treated with IL-1β. In these cells, expression of NLRP3 and p20 was significantly increased, NF-κB signaling was involved in this regulation, and mitochondrial reactive oxygen species(mt ROS)production increased. Furthermore, we found that melatonin disrupted the IL-1β/NF-κB-NLRP3 inflammasome activation positive feedback loop in vitro and in vivo. Melatonin treatment decreased NLRP3, p20, and IL-1β levels by inhibiting NF-κB signaling and downregulating mt ROS production. Finally, we showed that melatonin mediated the disruption of the positive feedback loop of IL-1β in vivo. In this study, we showed for the first time that IL-1β promotes its own expression by upregulating NLRP3 inflammasome activation. Furthermore, melatonin disrupts the IL-1β positive feedback loop and may be a potential therapeutic agent for IVDD.
文摘Lower back pain is a leading cause of disability and is one of the reasons for the substantial socioeconomic burden.The etiology of intervertebral disc(IVD)degeneration is complicated,and its mechanism is still not completely understood.Factors such as aging,systemic inflammation,biochemical mediators,toxic environmental factors,physical injuries,and genetic factors are involved in the progression of its pathophysiology.Currently,no therapy for restoring degenerated IVD is available except pain management,reduced physical activities,and surgical intervention.Therefore,it is imperative to establish regenerative medicine-based approaches to heal and repair the injured disc,repopulate the cell types to retain water content,synthesize extracellular matrix,and strengthen the disc to restore normal spine flexion.Cellular therapy has gained attention for IVD management as an alternative therapeutic option.In this review,we present an overview of the anatomical and molecular structure and the surrounding pathophysiology of the IVD.Modern therapeutic approaches,including proteins and growth factors,cellular and gene therapy,and cell fate regulators are reviewed.Similarly,small molecules that modulate the fate of stem cells for their differentiation into chondrocytes and notochordal cell types are highlighted.
