Degenerative Intervertebral Disc Disease Research Articles

Identification of Biomarkers, Pathways, Immune Properties of Mitophagy Genes, and Prediction Models for Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IDD) is the leading cause of low back pain (LBP). The mechanism of IDD development and progression is not fully understood. Peripheral biomarkers are increasingly vital non-radioactive methods in early detection and diagnosis for IDD. Nevertheless, less attention has been paid to the role of mitophagy genes in the progress of IDD. This study aimed to identify the mitophagy disease-causing genes in the process of IDD and mitophagy diagnostic biomarkers for IDD. Mitophagy-related differentially expressed genes (MRDEGs) related to IDD were investigated by analyzing the microarray datasets of IDD cases from GEO, PathCards and Molecular Signatures Databases. We used R software, WGCNA, PPI, mRNA-miRNA, mRNA-TF, GO, KEGG, GSEA, GSVA and Cytoscape to analyze and visualize the data. We further used ssGSEA for immunoinfiltration analysis to obtain different immune cell infiltration. LASSO model was developed to screen for genes that met the diagnostic gene model requirements. Finally, qRT-PCR, Western blotting and HE were used to verify hub genes and their expression from clinical IDD samples. We identified 14 MRDEGs and 12 hub genes. GO, KEGG, GSEA and GSVA analyses demonstrated that hub genes were critical for the development of IDD. LASSO diagnostic model consisted of six hub genes, among which SQSTM1, ATG7 and OPTN were significantly different between the two IDD disease subtypes. At the same time, SQSTM1 also had a high correlation with immune characteristic subtypes. The results of qRT-PCR and Western blotting also indicated that these genes were significantly differentially expressed in nucleus pulposus cells (NPCs) of the IDD group. We explored an association between MRDEGs-associated signature in IDD and validated that hub genes like SQSTM1 might serve as biomarkers for diagnostic and therapeutic targets for IDD. Meanwhile, this study can provide new insights into the functional characteristics and mechanism of mitophagy in the development of IDD.

Mesenchymal stem cell-derived exosomes are beneficial to suppressing inflammation and promoting autophagy in intervertebral disc degeneration.

Intervertebral disc degenerative diseases is one the main causes of lumbago, and its main pathological mechanism is intervertebral disc degeneration (IDD). As shown in previous reports, mesenchymal stem cell (MSC)-exosomes can slow down or even reverse degenerated nucleus pulposus (NP) cells in IDD. Thus, we attempted to clarify the specific role of MSC-exosomes underlying IDD progression. In the present study, the harvested particles were identified as MSC-exosomes. MSC-exosomes facilitated activation of autophagy pathway in AGE-treated NP cells. MSC-exosomes repressed inflammatory response in AGE-treated NP cells. Autophagy pathway activation enhanced inflammatory response in AGE-stimulated NP cells. Mesenchymal stem cell-exosomes facilitated autophagy pathway activation and repressed inflammation in IDD rats. Autophagy inhibition exerted a protective role against inflammatory response in IDD rats. In conclusion, MSC-exosomes represses inflammation via activating autophagy pathway, which provides a potential novel insight for seeking therapeutic plans of IDD.

Analysis of the causes of cage subsidence after oblique lateral lumbar interbody fusion

To observe the cage subsidence after oblique lateral interbody fusion (OLIF) for lumbar spondylosis, summarize the characteristics of the cage subsidence, analyze causes, and propose preventive measures. The data of 144 patients of lumbar spine lesions admitted to our hospital from October 2015 to December 2018 were retrospectively analyzed. There were 43 males and 101 females, and the age ranged from 20 to 81 years old, with an average of (60.90±10.06) years old. Disease types:17 patients of lumbar intervertebral disc degenerative disease, 12 patients of giant lumbar disc herniation, 5 patients of discogenic low back pain, 33 patients of lumbar spinal stenosis, 26 patients of lumbar degenerative spondylolisthesis, 28 patients of lumbar spondylolisthesis with spondylolisthesis, 11 patients of adjacent vertebral disease after lumbar internal fixation, 7 patients of primary spondylitis in the inflammatory outcome stage, and 5 patients of lumbar degenerative scoliosis. Preoperative dual-energy X-ray bone mineral density examination showed 57 patients of osteopenia or osteoporosis, and 87 patients of normal bone density. The number of fusion segments:124 patients of single-segment, 11 patients of two-segment, 8 patients of three-segment, four-segment 1 patient. There were 40 patients treated by stand-alone OLIF, and 104 patients by OLIF combined with posterior pedicle screw. Observed the occurrence of fusion cage settlement after operation, conducted monofactor analysis on possible risk factors, and observed the influence of fusion cage settlement on clinical results. All operations were successfully completed, the median operation time was 99 min, and the median intraoperative blood loss was 106 ml. Intraoperative endplate injury occurred in 30 patients and vertebral fracture occurred in 5 patients. The mean follow-up was (14.57±7.14) months from 6 to 30 months. During the follow-up, except for the patients of primary lumbar interstitial inflammation and some patients of lumbar spondylolisthesis with spondylolisthesis, the others all had different degrees of cage subsidence. Cage subsidence classification:119 patients were normal subsidence, and 25 patients were abnormal subsidence (23 patients were gradeⅠ, and 2 patients were gradeⅡ). There was no loosening or rupture of the pedicle screw system. The height of the intervertebral space recovered from the preoperative average (9.48±1.84) mm to the postoperative average (12.65±2.03) mm, and the average (10.51±1.81) mm at the last follow-up. There were statistical differences between postoperative and preoperative, and between the last follow-up and postoperative. The interbody fusion rate was 94.4%. The low back pain VAS decreased from the preoperative average (6.55±2.2 9) to the last follow-up (1.40±0.82), and there was statistically significant different. The leg pain VAS decreased from the preoperative average (4.72±1.49) to the final follow-up (0.60±0.03), and the difference was statistically significant (t=9.13, P<0.000 1). The ODI index recovered from the preoperative average (38.50±6.98)% to the latest follow-up (11.30±3.27)%, and there was statistically significant different. The complication rate was 31.3%(45/144), and the reoperation rate was 9.72%(14/144). Among them, 8 patients were reoperated due to fusion cage subsidence or displacement, accounting for 57.14%(8/14) of reoperation. The fusion cage subsidence in this group had obvious characteristics. The monofactor analysis showed that the number of abnormal subsidence patients in the osteopenia or osteoporosis group, Stand-alone OLIF group, 2 or more segments fusion group, and endplate injury group was higher than that in the normal bone mass group, OLIF combined with pedicle screw fixation group, single segment fusion group, and no endplate injury group, and the comparison had statistical differences. Cage subsidence is a common phenomenon after OLIF surgery. Preoperative osteopenia or osteoporosis, Stand-alone OLIF, 2 or more segments of fusion and intraoperative endplate injury may be important factors for postoperative fusion cage subsidence. Although there is no significant correlation between the degree of cage subsidence and clinical symptoms, there is a risk of cage migration, and prevention needs to be strengthened to reduce serious complications caused by fusion of cage subsidence, including reoperation.

Bicomponent hydrogel laden with TGF-β3-nucleus pulposus stem cells for disc degeneration repair

Degenerative intervertebral disc (IVD) disease, which cannot be completely treated with open or minimally invasive surgery, is primarily caused by nucleus pulposus (NP) degeneration. Meanwhile, NP regeneration requires the intricate coordination of stem cells, growth factors, and biomaterials. The current study sought to develop a regenerative approach for IVD degeneration. To this end, we used a lentiviral vector to introduce the transforming growth factor-β3 (TGF-β3) gene into NP mesenchymal stem cells (NPMSCs) to construct genetically modified seed cells. In addition, bicomponent gelatin methacrylate/hyaluronic acid methacrylate (GH) hydrogels were synthesized based on gelatin methacrylate (GelMA) and hyaluronic acid methacrylate (HAMA) precursors as carriers for TGF-β3-NPMSCs delivery. In vitro differentiation of the loaded stem cells into NP-like structures was improved by the hydrogels' superior mechanical and cytocompatibility features. Moreover, the stem cell-loaded GH hydrogel was delivered to NP tissue via a minimally invasive approach to construct an injectable “transgenic cell-hydrogel” in situ microenvironment, which attenuated IVD degeneration, preserved the integrity of the NP tissue, and sped up extracellular matrix synthesis in a rat model. Collectively, the results of this study demonstrate the potential of this novel therapeutic strategy as an effective regenerative approach for IVD degeneration.

Melatonin alleviates oxidative stress-induced injury to nucleus pulposus-derived mesenchymal stem cells through activating PI3K/Akt pathway

BackgroundThe changes in the microenvironment of degenerative intervertebral discs cause oxidative stress injury and excessive apoptosis of intervertebral disc endogenous stem cells. The purpose of this study was to explore the possible mechanism of the protective effect of melatonin on oxidative stress injury in NPMSCs induced by H2O2. MethodsThe Cell Counting Kit-8 assay was used to evaluate the cytotoxicity of hydrogen peroxide and the protective effects of melatonin. ROS content was detected by 2′7′-dichlorofluorescin diacetate (DCFH-DA). Mitochondrial membrane potential (MMP) was detected by the JC-1assay. Transferase mediated d-UTP Nick end labeling (TUNEL) and Annexin V/PI double staining were used to determine the apoptosis rate. Additionally, apoptosis-associated proteins and PI3K/Akt signaling pathway-related proteins were evaluated by immunofluorescence, immunoblotting and PCR. ECMs were evaluated by RT‒PCR and immunofluorescence. In vivo, X-ray, Magnetic resonance imaging (MRI) and Histological analyses were used to evaluate the protective effect of melatonin. ResultsMelatonin had an obvious protective effect on NPMSCs treated with 0–10 μM melatonin for 24 h. In addition, melatonin also had obvious protective effects on mitochondrial dysfunction, decreased membrane potential and cell senescence induced by H2O2. More importantly, melatonin could significantly reduce the apoptosis of nucleus pulposus mesenchymal stem cells induced by H2O2 by regulating the expression of apoptosis-related proteins and decreasing the rate of apoptosis. After treatment with melatonin, the PI3K/Akt pathway was significantly activated in nucleus pulposus mesenchymal stem cells, while the protective effect was significantly weakened after PI3K-IN-1 treatment. In vivo, the results of X-ray, MRI and histological analyses showed that therapy with melatonin could partially reduce the degree of intervertebral disc degeneration. ConclusionOur research demonstrated that melatonin can effectively alleviate the excessive apoptosis and mitochondrial dysfunction of nucleus pulposus mesenchymal stem cells induced by oxidative stress via the PI3K/Akt pathway, which provides a novel idea for the therapy of intervertebral disc degeneration. The translational potential of this articleThis study indicates that melatonin can effectively alleviate the excessive apoptosis and mitochondrial dysfunction of NPMSCs through activating the PI3K/Akt pathway. Melatonin might serve as a promising candidate for the prevention and treatment of Intervertebral disc degeneration disease (IVDD) in the future.

GelMA hydrogel scaffold containing curcumin-loaded solid lipid nanoparticles promotes the regeneration of degenerative discs

Intervertebral disc degenerative disease (IDD), which usually causes lower back and neck pain, is one of the most widespread musculoskeletal disorders and often causes a low quality of life. However, the surgical and conservative treatments commonly used in clinical practice are not effective. Previous studies have identified curcumin (Cur) as a potential therapeutic agent. However, its development in this regard has been limited due to its low dissolution, instability in water, and rapid metabolism. In this study, we developed a novel anti-inflammatory composite hydrogel scaffold with curcumin encapsulated in solid lipid nanoparticles and mixed it with gelatin methacrylate (GelMA) hydrogel to treat IDD. The hydrogel scaffold, denoted Cur-solid lipid nanoparticles (SLNs)/GelMA, promoted the restoration of Collagen type II (Col II) and aggrecan expression levels in vivo, indicating that the regeneration of the intervertebral discs was effective. Combined in vitro studies showed that Cur-SLNs inhibited the expression of the inflammatory factors TNF-α and IL-6. Additionally, immunofluorescence and western blotting experiments verified that Cur-SLNs regulated the recovery of Col II and aggrecan in an inflammatory environment and promoted the metabolic homeostasis of the extramedullary cell matrix. In conclusion, this study provides a new strategy to promote IDD regeneration, which brings new application prospects.

In situ forming macroporous biohybrid hydrogel for nucleus pulposus cell delivery

Degenerative intervertebral disc disease is a common source of chronic pain and reduced quality of life in people over the age of 40. While degeneration occurs throughout the disc, it most often initiates in the nucleus pulposus (NP). Minimally invasive delivery of NP cells within hydrogels that can restore and maintain the disc height while regenerating the damaged NP tissue is a promising treatment strategy for this condition. Towards this goal, a biohybrid ABA dimethacrylate triblock copolymer was synthesized, possessing a lower critical solution temperature below 37 °C and which contained as its central block an MMP-degradable peptide flanked by poly(trimethylene carbonate) blocks bearing pendant oligoethylene glycol groups. This triblock prepolymer was used to form macroporous NP cell-laden hydrogels via redox initiated (ammonium persulfate/sodium bisulfite) crosslinking, with or without the inclusion of thiolated chondroitin sulfate. The resulting macroporous hydrogels had water and mechanical properties similar to those of human NP tissue and were mechanically resilient. The hydrogels supported NP cell attachment and growth over 28 days in hypoxic culture. In hydrogels prepared with the triblock copolymer but without the chondroitin sulfate the NP cells were distributed homogeneously throughout in clusters and deposited collagen type II and sulfated glycosaminoglycans but not collagen type I. This hydrogel formulation warrants further investigation as a cell delivery vehicle to regenerate degenerated NP tissue. Statement of significanceThe intervertebral disc between the vertebral bones of the spine consists of three regions: a gel-like central nucleus pulposus (NP) within the annulus fibrosis, and bony endplates. Degeneration of the intervertebral disc is a source of chronic pain in the elderly and most commonly initiates in the NP. Replacement of degenerated NP tissue with a NP cell-laden hydrogel is a promising treatment strategy. Herein we demonstrate that a crosslinkable polymer with a lower critical solution temperature below 37 °C can be used to form macroporous hydrogels for this purpose. The hydrogels are capable of supporting NP cells, which deposit collagen II and sulfated glycosaminoglycans, while also possessing mechanical properties matching those of human NP tissue.

Pharmacological network analysis of the functions and mechanism of kaempferol from Du Zhong in intervertebral disc degeneration (IDD).

Senescence and apoptosis of the nucleus pulposus cells (NPCs) are essential components of the intervertebral disc degeneration (IDD) process. Senescence and anti-apoptosis treatments could be effective ways to delay or even stop disc degeneration. IDD has been treated with Eucommia ulmoides Oliver (Du Zhong, DZ) and its active ingredients. However, the roles and mechanisms of DZ in NPC apoptosis and senescence remain unclear. Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was used to select the main active ingredients of DZ with the threshold of oral bioavailability (OB)​≥​30% and drug-likeness (DL)​≥​0.2. GSE34095 contained expression profile of degenerative intervertebral disc tissues and non-degenerative intervertebral disc tissues were downloaded for different expression genes analysis. The disease targets genes of IDD were retrieved from GeneCards. The online tool Metascape was used for functional enrichment annotation analysis. The specific effects of the ingredient on IL-1β treated NPC cell proliferation, cell senescence, reactive oxygen species (ROS) accumulation and cell apoptosis were determined by CCK-8, SA-β-gal staining, flowcytometry and western blot assays. A total of 8 active compounds of DZ were found to meet the threshold of OB​≥​30% and DL​≥​0.2 with 4151 drug targets. After the intersection of 879 IDD disease targets obtained from GeneCards and 230 DEGs obtained from the IDD-related GSE dataset, a total of 13 hub genes overlapped. According to functional enrichment annotation analysis by Metascape, these genes showed to be dramatically enriched in AGE-RAGE signaling, proteoglycans in cancer, wound healing, transmembrane receptor protein tyrosine kinase signaling, MAPK cascades, ERK1/2 cascades, PI3K/Akt signaling pathway, skeletal system, etc. Disease association analysis by DisGeNET indicated that these genes were significantly associated with IDD, intervertebral disc disease, skeletal dysplasia, and other diseases. Active ingredients-targets-signaling pathway networks were constructed by Cytoscape, and kaempferol was identified as the hub active compound of DZ. In the IL-1β-induced IDD in vitro model, kaempferol treatment significantly improved IL-1β-induced NPC cell viability suppression and senescence. In addition, kaempferol treatment significantly attenuated IL-1β-induced ROS accumulation and apoptosis. Furthermore, kaempferol treatment partially eliminated IL-1β-induced decreases in aggrecan, collagen II, SOX9, and FN1 levels and increases in MMP3, MMP13, ADAMTS-4, and ADAMTS-5. Moreover, kaempferol treatment significantly relieved the promotive effects of IL-1β stimulation upon p38, JNK, and ERK1/2 phosphorylation. ERK1/2 inhibitor PD0325901 further enhanced the effect of kaempferol on the inhibition of ERK1/2 phosphorylation, downregulation of MMP3 and ADAMTS-4 expression, and upregulation of aggrecan and collagen II expressions. Kaempferol has been regarded as the major active compound of DZ, protecting NPCs from IL-1β-induced damages through promoting cell viability, inhibiting cell senescence and apoptosis, increasing ECM production, and decreasing ECM degradation. MAPK signaling pathway may be involved. This study provides in vitro experimental data support for the pharmacological effects of kaempferol in treating IDD, and lays a solid experimental foundation for its future clinical application in IDD treatment.

Evaluation of the concentration of growth associated protein-43 and glial cell-derived neurotrophic factor in degenerated intervertebral discs of the lumbosacral region of the spine.

Important neurotrophic factors that are potentially involved in degenerative intervertebral disc (IVD) disease of the spine's lumbosacral (L/S) region include glial cell-derived neurotrophic factor (GDNF) and growth associated protein 43 (GAP-43). The aim of this study was to determine and compare the concentrations of GAP-43 and GDNF in degenerated and healthy IVDs and to quantify and compare the GAP-43-positive and GDNF-positive nerve fibers. The study group consisted of 113 Caucasian patients with symptomatic lumbosacral discopathy (confirmed by a specialist surgeon), an indication for surgical treatment. The control group included 81 people who underwent postmortem examination. GAP-43 and GDNF concentrations were significantly higher in IVD samples from the study group compared with the control group, and the highest concentrations were observed in the degenerated IVDs that were graded 4 on the Pfirrmann scale. In the case of GAP-43, it was found that as the degree of IVD degeneration increased, the number of GAP-43-positive nerve fibers decreased. In the case of GDNF, the greatest number of fibers per mm2 of surface area was found in the IVD samples graded 3 on the Pfirrmann scale, and the number was found to be lower in samples graded 4 and 5. Hence, GAP-43 and GDNF are promising targets for analgesic treatment of degenerative IVD disease of the lumbosacral region of the spine.

Progranulin in Musculoskeletal Inflammatory and Degenerative Disorders, Focus on Rheumatoid Arthritis, Lupus and Intervertebral Disc Disease: A Systematic Review.

Progranulin (PGRN) is a glycoprotein formed by 593 amino acids encoded by the GRN gene. It has an important role in immunity and inflammatory response, as well as in tissue recovery. Its role in musculoskeletal inflammatory diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and intervertebral disc degeneration disease (IVDD), is, nowadays, an important target to investigate. The objective of this review is to systematically sum up all the recent findings concerning PGRN as a target in the development and resolution of the inflammatory diseases. PubMed was examined with the terms combinations (Progranulin) AND (Lupus Erythematosus, Systemic), (Progranulin) AND (Arthritis, Rheumatoid), and (Progranulin) AND (Intervertebral Disc Degeneration). PubMed was examined with the terms combinations (Atsttrin) AND (Lupus Erythematosus, Systemic), (Atsttrin) AND (Arthritis, Rheumatoid), and (Atsttrin) AND (Intervertebral Disc Degeneration). Moreover, research through Web of Science was performed searching the same items. The inclusion criteria were: studies whose main topic were progranulin, or atsttrin, with emphasis on the three selected diseases. On the other hand, the exclusion criteria were studies that only focused on diseases not related to RA, lupus or IVDD, in addition to the previous published literature reviews. Since few results were obtained, we did not filter by year. The records assessed for eligibility were 23, including all the studies with the information in state of art of progranulin and its capability to be a potential target or treatment for each one of the selected diseases. As these results are descriptive and not clinical trials, we did not perform risk of bias methods. Within these results, many studies have shown an anti-inflammatory activity of PGRN in RA. PGRN levels in serum and synovial fluids in RA patients were reported higher than controls. On the other hand, serum levels were directly correlated with SLE disease activity index, suggesting an important role of PGRN as a player in the progression of inflammatory diseases and a therapeutical approach for the recovery. This review has some limitations due to the small number of studies in this regard; therefore, we highlight the importance and the necessity of further investigation. No external funding was implicated in this systematical review.

Nucleus pulposus cells degeneration model: a necessary way to study intervertebral disc degeneration.

The availability of an appropriate and reliable research model is helpful for researchers to understand the occurrence and development of diseases. Historically, animal models have been beneficial in the study of intervertebral disc degenerative diseases, but intervertebral disc degeneration (IDD) is a precise and complex process that needs to appear and occur in a specific tissue microenvironment, and animal degeneration models cannot fully simulate these parameters. These challenges must be overcome, especially when animal models cannot fully generalise the complex pathology of humans. In the past few years, the research on the cell disease model has made important progress, and the construction of the nucleus pulposus cell (NPC) degeneration model has become an indispensable step in studying the occurrence and development of IDD. Here, several different methods of constructing NPC degeneration models and indicators for testing the effect of modelling are introduced. The practical applications of cell models constructed by different methods are enumerated to screen and evaluate effective methods of establishing degenerative cell models and explore the mechanism of IDD.

Case-control study on endplate injury of lumbar spine with two different intervertebral fusion methods

To summarize and compare the endplate injury occurrence characteristics and clinical results of transforaminal intervertebral fusion combined with pedicle screw fixation through intermuscular approach and oblique lateral intervertebral fusion combined with pedicle screw fixation in the treatment of lumbar disease. A retrospective analysis of 213 cases of lumbar disease admitted from January 2016 to June 2019, including 73 males and 140 females. The age ranged from 24 to 81 years old, with an average of(54.9±10.5) years old. The courses of disease ranged from 6 to 180 months, with an average of (40.30±28.71) months. There were 35 cases of degenerative lumbar intervertebral disc disease, 22 cases of giant lumbar disc herniation, 15 cases of discogenic low back pain, 9 cases of primary lumbar intervertebral inflammation at the turn of inflammation, 52 cases of lumbar spinal stenosis, 47 cases of lumbar degenerative spondylolisthesis, 33 cases of lumbar spondylolysis with or without spondylolisthesis. There were 191 cases of single-segment lesions, including 5 cases on L2, 3, 24 cases on L3, 4, 162 cases on L4, 5. And there were 22 cases of two-segment lesions, including 3 cases on L2, 3 and L3, 4, and 19 cases on L3, 4 and L4, 5. One hundred and ten cases were taken by bilateral pedicle screw fixation and interbody fusion under the posterior muscle space approach (abbreviated as posterior fusion group), and 103 cases were taken by oblique lateral interbody fusion combined with bilateral pedicle screw fixation under the posterior muscle space approach (oblique lateral fusion group). Observed the characteristics of endplate injury in the two groups, and compared the clinical and imaging results and complications of the two groups. There were 8 cases of endplate injury occurred in 9 segments in the posterior fusion group. According to the number of cases, the incidence rate was 7.27%(8/110), 1 case was male, 7 cases were female, with an average age of (63.22±3.51) years old. Among the 8 cases, there were 7 cases of bone loss or osteoporosis before the operation, 5 cases using banana fusion cages, 3 cases using anatomical fusion cages. Three cases occurred in the upper endplate of the vertebral body and 6 cases in the inferior endplate of the vertebral body. In the oblique lateral fusion group, there were 21 cases of endplate injury in 24 segments, and the incidence rate was 20.39%(21/103). There were 4 males and 17 females, with an average age of (62.50±5.02) years old. Among the 21 cases, 16 cases were bone loss or osteoporosis before operation. There were 5 cases used large fusion cages, 4 cases had abnormal endplate anatomy, and 3 cases had iliac crest hypertrophy. It occurred in 20 segments of the upper endplate of the vertebral body, and 4 segments of the lower endplate of the vertebral body. Two of the 21 cases of endplate injury combined with vertebral body fractures. The incidence of endplate injury of the posterior fusion group was significantly lower than that of the oblique lateral fusion group. No incision infection occurred in the two groups, the follow-up time was ranged from 12 to 48 months, and the median follow-up period was 12 months. In the follow-up, 22 cases occurred fusion cage subsidence in the posterior fusion group, 43 cases in the oblique lateral fusion group, and 1 case in each group occurred fusion cage displacement. There was no loosening, displacement or breakage of the internal fixation. The incidence of complications in the oblique lateral fusion group 33.98%(35/103) was significantly higher than that in the posterior fusion group 23.64%(26/110), P=0.039. The height of the intervertebral space in both groups recovered well after the operation, but it was lost to varying degrees during follow-up. The fusion rate of the posterior fusion group was 94.5%(104/110), and 96.1%(99/103) in the oblique lateral fusion group(P=0.083). At the latest follow-up, the clinical symptoms of the two groups of patients were significantly improved. Two methods in treating single or two-segment lumbar spine lesions obtained good clinical effects. The characteristics of endplate injury in the two fusion methods are not completely the same. Although the endplate injury did not affect the final clinical results of the two fixed fusion methods, it still needs to be paid attention to and emphasize the prevention and effective treatment of endplate injury, especially for oblique lateral intervertebral fusion.

Joint degeneration cycle: A novel educational model with degenerative intervertebral disc disease as an example

Joint degeneration cycle: A novel educational model with degenerative intervertebral disc disease as an example

Elimination of Senescent Cells by Senolytics Facilitates Bony Endplate Microvessel Formation and Mitigates Disc Degeneration in Aged Mice

Senolytics are a class of drugs that selectively eliminate senescent cells and ameliorate senescence-associated disease. Studies have demonstrated the accumulation of senescent disc cells and the production of senescence-associated secretory phenotype decrease the number of functional cells in degenerative tissue. It has been determined that clearance of senescent cell by senolytics rejuvenates various cell types in several human organs, including the largest avascular structure, intervertebral disc (IVD). The microvasculature in the marrow space of bony endplate (BEP) are the structural foundation of nutrient exchange in the IVD, but to date, the anti-senescence effects of senolytics on senescent vascular endothelial cells in the endplate subchondral vasculature remains unclear. In this study, the relationships between endothelial cellular senescence in the marrow space of the BEP and IVD degeneration were investigated using the aged mice model. Immunofluorescence staining was used to evaluate the protein expression of P16, P21, and EMCN in vascular endothelial cells. Senescence-associated β-galactosidase staining was used to investigate the senescence of vascular endothelial cells. Meanwhile, the effects of senolytics on cellular senescence of human umbilical vein endothelial cells were investigated using a cell culture model. Preliminary results showed that senolytics alleviate endothelial cellular senescence in the marrow space of BEP as evidenced by reduced senescence-associated secretory phenotype. In the aged mice model, we found decreased height of IVD accompanied by vertebral bone mass loss and obvious changes to the endplate subchondral vasculature, which may lead to the decrease in nutrition transport into IVD. These findings may provide evidence that senolytics can eliminate the senescent cells and facilitate microvascular formation in the marrow space of the BEP. Targeting senescent cellular clearance mechanism to increase nutrient supply to the avascular disc suggests a potential treatment value of senolytics for IVD degenerative diseases.

Injectable Hydrogels for Articular Cartilage and Nucleus Pulposus Repair: Status Quo and Prospects.

Osteoarthritis (OA) and chronic low back pain due to degenerative (intervertebral) disc disease (DDD) are two of the major causes of disabilities worldwide, affecting hundreds of millions of people and leading to a high socioeconomic burden. Although OA occurs in synovial joints and DDD occurs in cartilaginous joints, the similarities are striking, with both joints showing commonalities in the nature of the tissues and in the degenerative processes during disease. Consequently, repair strategies for articular cartilage (AC) and nucleus pulposus (NP), the core of the intervertebral disc, in the context of OA and DDD share common aspects. One of such tissue engineering approaches is the use of injectable hydrogels for AC and NP repair. In this review, the state-of-the-art and recent developments in injectable hydrogels for repairing, restoring, and regenerating AC tissue suffering from OA and NP tissue in DDD are summarized focusing on cell-free approaches. The various biomaterial strategies exploited for repair of both tissues are compared, and the synergies that could be gained by translating experiences from one tissue to the other are identified. Impact statement Joints affected by osteoarthritis (OA) and degenerative (intervertebral) disc disease (DDD) share similarities in tissue composition and in the degenerative disease processes. This has led to the development of similar tissue engineering approaches to repair the articular cartilage (AC) and the nucleus pulposus (NP), in the context of OA and DDD, such as injectable hydrogels. In this review, recent developments in injectable hydrogels for repair of AC and NP tissues are summarized, biomaterial strategies are compared, and synergies are identified focusing on cell-free approaches. The summarized developments are expected to inspire more cross talk between both research fields.

Protective Effects of Growth Differentiation Factor-6 on the Intervertebral Disc: An In Vitro and In Vivo Study.

Growth differentiation factors (GDFs) regulate homeostasis by amplifying extracellular matrix anabolism and inhibiting pro-inflammatory cytokine production in the intervertebral disc (IVD). The aim of this study was to elucidate the effects of GDF-6 on human IVD nucleus pulposus (NP) cells using a three-dimensional culturing system in vitro and on rat tail IVD tissues using a puncture model in vivo. In vitro, Western blotting showed decreased GDF-6 expression with age and degeneration severity in surgically collected human IVD tissues (n = 12). Then, in moderately degenerated human IVD NP cells treated with GDF-6 (100 ng/mL), immunofluorescence demonstrated an increased expression of matrix components including aggrecan and type II collagen. Quantitative polymerase chain reaction analysis also presented GDF-6-induced downregulation of pro-inflammatory tumor necrosis factor (TNF)-α (p = 0.014) and interleukin (IL)-6 (p = 0.016) gene expression stimulated by IL-1β (10 ng/mL). Furthermore, in the mitogen-activated protein kinase pathway, Western blotting displayed GDF-6-induced suppression of p38 phosphorylation (p = 0.041) under IL-1β stimulation. In vivo, intradiscal co-administration of GDF-6 and atelocollagen was effective in alleviating rat tail IVD annular puncture-induced radiologic height loss (p = 0.005), histomorphological degeneration (p < 0.001), matrix metabolism (aggrecan, p < 0.001; type II collagen, p = 0.001), and pro-inflammatory cytokine production (TNF-α, p < 0.001; IL-6, p < 0.001). Consequently, GDF-6 could be a therapeutic growth factor for degenerative IVD disease.

Reparative effects of chronic intermittent hypobaric hypoxia pre‑treatment on intervertebral disc degeneration in rats.

Previous studies have indicated that chronic intermittent hypobaric hypoxia (CIHH) preconditioning can inhibit TNF-α 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 Sprague-Dawley rats were selected and randomly divided into an experimental group (CIHH-IDD), a degenerative group (IDD) and a control group (CON). The CIHH-IDD 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 tail-vertebral 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 X-ray 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), TGFβ1, Collagen I and Collagen II were measured in the intervertebral disc tissue using western blotting; while the expression levels of bFGF, TGFβ1 and hypoxia-inducible factor 1-α (HIF-1α) were measured in rat serum using ELISA. The results demonstrated that: i) The degree of intervertebral disc height degeneration in CIHH-IDD rats was significantly lower compared with that in IDD rats (P<0.05); ii) the expression levels of bFGF, TGFβ1 and HIF-1α were higher in CIHH-IDD 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 CIHH-IDD rats; and iv) the protein expression levels of bFGF, TGFβ1 and collagen II were increased in CIHH-IDD rat intervertebral disc tissues compared with those of IDD rats, while the overexpression of collagen I protein was inhibited. Overall, after CIHH pre-treatment, the expression levels of bFGF and TGFβ1 were up-regulated, which play notable roles in repairing degenerative intervertebral discs in rats.

Biomaterials and Cell-Based Regenerative Therapies for Intervertebral Disc Degeneration with a Focus on Biological and Biomechanical Functional Repair: Targeting Treatments for Disc Herniation.

Intervertebral disc (IVD) degeneration is a common cause of low back pain and most spinal disorders. As IVD degeneration is a major obstacle to the healthy life of so many individuals, it is a major issue that needs to be overcome. Currently, there is no clinical treatment for the regeneration of degenerated IVDs. However, recent advances in regenerative medicine and tissue engineering suggest the potential of cell-based and/or biomaterial-based IVD regeneration therapies. These treatments may be indicated for patients with IVDs in the intermediate degenerative stage, a point where the number of viable cells decreases, and the structural integrity of the disc begins to collapse. However, there are many biological, biomechanical, and clinical challenges that must be overcome before the clinical application of these IVD regeneration therapies can be realized. This review summarizes the basic research and clinical trials literature on cell-based and biomaterial-based IVD regenerative therapies and outlines the important role of these strategies in regenerative treatment for IVD degenerative diseases, especially disc herniation.

Intervertebral Disc-on-a-Chip as Advanced In Vitro Model for Mechanobiology Research and Drug Testing: A Review and Perspective.

Discogenic back pain is one of the most diffused musculoskeletal pathologies and a hurdle to a good quality of life for millions of people. Existing therapeutic options are exclusively directed at reducing symptoms, not at targeting the underlying, still poorly understood, degenerative processes. Common intervertebral disc (IVD) disease models still do not fully replicate the course of degenerative IVD disease. Advanced disease models that incorporate mechanical loading are needed to investigate pathological causes and processes, as well as to identify therapeutic targets. Organs-on-chip (OoC) are microfluidic-based devices that aim at recapitulating tissue functions in vitro by introducing key features of the tissue microenvironment (e.g., 3D architecture, soluble signals and mechanical conditioning). In this review we analyze and depict existing OoC platforms used to investigate pathological alterations of IVD cells/tissues and discuss their benefits and limitations. Starting from the consideration that mechanobiology plays a pivotal role in both IVD homeostasis and degeneration, we then focus on OoC settings enabling to recapitulate physiological or aberrant mechanical loading, in conjunction with other relevant features (such as inflammation). Finally, we propose our view on design criteria for IVD-on-a-chip systems, offering a future perspective to model IVD mechanobiology.

Comparison between T2-weighted two-dimensional and three-dimensional fast spin-echo MRI sequences for characterizing thoracolumbar intervertebral disc disease in small-breed dogs.

Magnetic resonance imaging (MRI) is a standard test for diagnosis and treatment planning in dogs with degenerative thoracolumbar intervertebral disc disease (IVDD). However, published studies evaluating three-dimensional fast-spin echo (3D-FSE) pulse sequences for dogs with IVDD are currently limited. Aims of this retrospective, observational study were to compare findings from T2-weighted two- and three-dimensional fast spin-echo sequences (2D- and 3D-FSE, respectively) for a group of small breed dogs with thoracolumbar IVDD. Inclusion criteria were dogs with IVDD that underwent 1.5-Tesla MRI using both 2D-FSE and 3D-FSE sequences. For each dog and sequence, five pathologic indices were recorded: epidural fat discontinuation, vertebral canal compromise, spinal cord signal change, disc degeneration, and nerve root compression. Two independent investigators also scored visibility of the facet joint, intervertebral foramen, nerve roots, spinal cord grey-white matter differentiation, intervertebral discs, and epidural fat. The Wilcoxon signed-rank test was used to evaluate the between-sequence differences in pathologic indices and visibility scores. Interobserver agreement was measured using Cohen's weighted kappa along with 95% confidence intervals. A total of 21 dogs were sampled. The 3D-FSE sequences had higher pathologic indices of vertebral canal compromise (P=0.020) and spinal cord signal change (P=0.046) than 2D-FSE sequences. Furthermore, 3D-FSE sequences had higher visibility scores for the facet joint, intervertebral foramen, and nerve root structures (P<0.001). Findings from the current supported the use of 3D-FSE sequences over 2D-FSE sequences for the evaluation of IVDD and visualization of spinal structures in small breed dogs.