Disc Degeneration Research Articles

Effects of GDF6 on active protein synthesis by cells of degenerated intervertebral disc.

Intervertebral disc degeneration (IVD) is a leading cause of low back pain, a prevalent musculoskeletal condition. IVD degeneration is characterized by the degradation of nucleus pulposus (NP), annulus fibrosus (AF), and cartilage endplates (EP). Growth Differentiation Factor 6 (GDF6), part of the bone morphogenetic protein family, has demonstrated potential in maintaining disc integrity. However, its precise role in cellular protein synthesis during IVD degeneration remains unclear. This study employed Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) to investigate the effects of GDF6 on protein synthesis in NP, AF, and EP cells isolated from degenerated human IVDs. Cells were cultured in SILAC media with and without GDF6 treatment. The proteomic profiles were analyzed via mass spectrometry, comparing newly synthesized "heavy" proteins with pre-existing "light" proteins. GDF6 treatment altered protein synthesis in degenerated IVD cells. In NP cells, GDF6 reduced the synthesis of matrisome proteins, including collagens and proteoglycans, while promoting proteins associated with ECM stability, such as LOX, PCOLCE and HAPLN1/3. AF cells demonstrated an upregulation of ECM-stabilizing proteins like POSTN and FMOD. EP cells showed minimal changes, but GDF6 enhanced the synthesis of collagen type II, suggesting improved ECM integrity. Secretome analysis revealed that GDF6 modulated extracellular signalling by promoting ECM-stabilizing proteins and reducing inflammatory markers. GDF6 exerts compartment-specific effects on protein synthesis in degenerated IVDs, promoting ECM stability, reducing fibrosis, and potentially preserving hydration. These findings support the potential of GDF6 as a therapeutic agent in treating IVD degeneration, particularly in NP-targeted therapies. Future studies should optimize GDF6 dosing and delivery to maximize its regenerative potential.

O-GlcNAcylation: Sagacious Orchestrator of Bone-, Joint-, and Spine-Related Diseases.

O-linked beta-N-acetylglucosamine glycosylation (O-GlcNAcylation), a post-translational modification of proteins, occurs in multiple physiological and pathological processes. Despite comprehensive study of protein modifications, such as phosphorylation, acetylation, and ubiquitination in musculoskeletal diseases, the role of O-GlcNAcylation in this field has been largely overlooked. However, in recent years, several studies have initially elucidated the biological mechanisms through which O-GlcNAcylation regulates the development and progress of musculoskeletal diseases, including osteoarthritis, osteoporosis, osteosarcoma, and intervertebral disc degeneration. This review aims to systematically and comprehensively summarize the existing evidence, sketching the contours of the underlying mechanisms and related signaling pathways, discussing the limitations and controversies, and providing guidance for future studies on the role of O-GlcNAcylation modifications in musculoskeletal diseases.

CircSPG21 ameliorates oxidative stress-induced senescence in nucleus pulposus-derived mesenchymal stem cells and mitigates intervertebral disc degeneration through the miR-217/SIRT1 axis and mitophagy

BackgroundThe microenvironment of intervertebral disc degeneration (IVDD) is characterized by oxidative stress, leading to the senescence of nucleus pulposus-derived mesenchymal stem cells (NPMSCs). The purpose of this study was to investigate the competitive endogenous RNA mechanism involved in the senescence of NPMSCs induced by tert-butyl hydroperoxide (TBHP).MethodsBioinformatic analysis identified differentially expressed circRNAs. Interactions among circSPG21, miR-217, and the NAD-dependent protein deacetylase sirtuin-1 (SIRT1) were validated through dual-luciferase assays, RNA fluorescence in situ hybridization and RNA immune precipitation. β-Gal staining, EdU staining, Western blotting, JC-1 assays, cell cycle analysis, and quantitative reverse transcription PCR (RT‒qPCR) were used to examine the functions of these molecules in TBHP-induced senescent NPMSCs. The therapeutic effects of circSPG21 were evaluated in a rat IVDD model.ResultsCircSPG21 expression was significantly decreased in both human and rat IVDD tissues, whereas miR-217 was upregulated and SIRT1 was downregulated. Overexpression of circSPG21 alleviated NPMSC senescence by reducing P21 and P53 levels and restoring mitophagy through Parkin. The protective effects of circSPG21 were mediated through the miR-217/SIRT1 axis, as SIRT1 knockdown attenuated these benefits. CircSPG21 also ameliorated disc degeneration in the IVDD rat model, highlighting its potential as a therapeutic target.ConclusionCircSPG21 reduces oxidative stress-induced NPMSC senescence through the miR-217/SIRT1 axis and mitophagy, providing new insights into IVDD and identifying circSPG21 as a potential therapeutic target for disc degeneration.

Morphologic Patterns of Spinal Degeneration and Trauma in a Nigerian Population: A Retrospective Radio-Anatomic Study.

Understanding the morphologic patterns of degenerative and traumatic spinal conditions is essential for precise diagnosis and management plans. This study evaluates the sequence of structural changes in degenerative spinal disorder patients' discovertebral unit and the traumatic spinal injury patterns in a northwestern Nigerian population. A hospital-based retrospective study reviewed radiologic images of 307 patients with spinal degeneration (n= 269) and trauma (n= 38) at 2 tertiary hospitals in northwest Nigeria. The study presented descriptive and inferential statistics, with a 95% confidence interval and significance level with a P value ≤0.05. The average age of patients with spinal degeneration was 52.5 years, with females (60.6%) and those aged 41 years and older (76.6%) predominant, whereas patients with trauma averaged 36.3 years and were predominantly male (78.9%) and aged 21-40 years (60.5%). Common clinical manifestations included radicular pain (53.9%) in degenerative cases and spinal shock (36.8%) in trauma. Correlation analysis showed significant links between mild/moderate straightening of spinal curvature and clinical manifestations (P= 0.001). Age-influenced osteophyte and intervertebral disc degeneration, especially in the group aged 41-60 years (P= 0.001), with AO/Magerl type A spinal injury, was more common in males (P= 0.022) and the group aged 21-40 years (P= 0.019), indicating notable demographic trends. Intervertebral disc degeneration peaks at L3, L4, and L5, notably grade III (P= 0.001), and Modic II frequencies increase from L1 (n= 16) to L5 (n= 35) without significant association (P= 0.99). This study showed different morphologic patterns in degenerative and traumatic spinal conditions in the study population, with considerable age, gender, and symptom correlations. These findings emphasize the importance of understanding these patterns for effective diagnosis and management strategies of spinal degeneration and trauma.

ISSLS Prize in Clinical Science 2025: Cartilage End Plate Defects Precede and Initiate Bony End Plate Defects and Disc Degeneration- An 'Integrated Total End Plate Score' Identify Preclinical Discs at Risk for Degeneration.

We utilized the Fast Low Angle Shot (FLASH) sequence to document the sequential changes in cartilaginous (CEP) and bony end plate (BEP) to study the influence on disc degeneration (DD). Routine MRI and FLASH sequences were used in 500 lumbar discs in 100 each of healthy volunteers (HV), low back pain patients treated conservatively (CG) and surgically (SG) to document CEP and BEP status, Pfirrmann Grade (PG) and various MRI parameters. The three groups were identical demographically but had a significantly different number of healthy discs (p < 0.01) and changes in CEP and BEP (p < 0.01), with patients having a higher severity of end plate changes and DD, even in asymptomatic discs. CEP abnormalities always appeared first, followed by a sequence of BEP defects of different severity, allowing the development of an 'Integrated Total End Plate Score' (I-TEPS). There was a good correlation between I-TEPS and PG, with a steep escalation of DD after a score of 7. A score of ≥ 7 was also associated with higher surgical incidence in patients with both degenerated and herniated discs. The most significant influencing factors for surgery was a combination of I-TEPS ≥ 7 with herniation (OR7.7;p-0.00), smoking (OR4.63;p-0.02), and an I-TEPS ≥ 7 (OR3.37;p-0.04). CEP changes identified by FLASH preceded BEP defects and DD. I-TEPS was superior to TEPS in identifying a subgroup of discs that had CEP abnormalities without BEP. An I-TEPS ≥ 7 had a significant correlation to the severity of DD, influenced variations in herniation and also surgical incidence.

WDRIV-Net: a weighted ensemble transfer learning to improve automatic type stratification of lumbar intervertebral disc bulge, prolapse, and herniation

The degeneration of the intervertebral discs in the lumbar spine is the common cause of neurological and physical dysfunctions and chronic disability of patients, which can be stratified into single—(e.g., disc herniation, prolapse, or bulge) and comorbidity-type degeneration (e.g., simultaneous presence of two or more conditions), respectively. A sample of lumbar magnetic resonance imaging (MRI) images from multiple clinical hospitals in China was collected and used in the proposal assessment. We devised a weighted transfer learning framework WDRIV-Net by ensembling four pre-trained models including Densenet169, ResNet101, InceptionV3, and VGG19. The proposed approach was applied to the clinical data and achieved 96.25% accuracy, surpassing the benchmark ResNet101 (87.5%), DenseNet169 (82.5%), VGG19 (88.75%), InceptionV3 (93.75%), and other state-of-the-art (SOTA) ensemble deep learning models. Furthermore, improved performance was observed as well for the metric of the area under the curve (AUC), producing a ≥ 7% increase versus other SOTA ensemble learning, a ≥ 6% increase versus most-studied models, and a ≥ 2% increase versus the baselines. WDRIV-Net can serve as a guide in the initial and efficient type screening of complex degeneration of lumbar intervertebral discs (LID) and assist in the early-stage selection of clinically differentiated treatment options.

Modic changes: From potential molecular mechanisms to future research directions (Review).

Low back pain (LBP) is a leading cause of disability worldwide. Although not all patients with Modic changes (MCs) experience LBP, MC is often closely associated with LBP and disc degeneration. In clinical practice, the focus is usually on symptoms related to MC, which are hypothesized to be associated with LBP; however, the link between MC and nerve compression remains unclear. In cases of intervertebral disc herniation, nerve compression is often the definitive cause of symptoms. Recent advances have shed light on the pathophysiology of MC, partially elucidating its underlying mechanisms. The pathogenesis of MC involves complex bone marrow‑disc interactions, resulting in bone marrow inflammation and edema. Over time, hematopoietic cells are gradually replaced by adipocytes, ultimately resulting in localized bone marrow sclerosis. This process creates a barrier between the intervertebral disc and the bone marrow, thereby enhancing the stability of the vertebral body. The latest understanding of the pathophysiology of MC suggests that chronic inflammation plays a significant role in its development and hypothesizes that the complement system may contribute to its pathological progression. However, this hypothesis requires further research to be confirmed. The present review we proposed a pathological model based on current research, encompassing the transition from Modic type 1 changes (MC1) to Modic type 2 changes (MC2). It discussed key cellular functions and their alterations in the pathogenesis of MC and outlined potential future research directions to further elucidate its mechanisms. Additionally, it reviewed the current clinical staging and pathogenesis of MC, recommended the development of an updated staging system and explored the prospects of integrating emerging artificial intelligence technologies.

Molecular mechanism of macrophage polarization regulating the cell senescence of nucleus pulposus during intervertebral disc degeneration.

In orthopedics, intervertebral disc degeneration (IVDD) is a prevalent chronic condition whose cellular molecular processes are yet unclear. The objective of this research was to uncover the molecular causes of aging and identify the immunological microenvironmental alterations and immune cell infiltration in IVDD. IVDD gene datasets were obtained using GeneCards, and gene expression profiles were chosen from the Gene Expression Synthesis database (GSE244889). The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) databases were used to examine biological processes. The analysis of immune cell infiltration was done using CIBERSORT. To shed light on the variations in cell types among intervertebral discs with varying degrees of degeneration, single-cell analysis was carried out. Lastly, it was confirmed in vitro that important proteins and genes were expressed. At first, 10 hub genes and 58 intersecting genes were found. Major biological processes include the inflammatory response, chemokine-mediated signaling pathways, and immune response. The three main signaling mechanisms in IVDD are HIF, apoptosis, and cellular senescence. Macrophages M0, M1, M2, T cells, CD4 memory resting, NK cells, T cells regulatory (Tregs), and T cells were all markedly infiltrated in IVDD patients. According to in vitro validation, the IVDD model group had higher levels of proteins linked to the immunological microenvironment. In conclusion, immune cell infiltration-particularly macrophage infiltration, which stimulates the release of inflammatory factors that cause the inflammatory response and cellular senescence in NPCs-is linked to the primary molecular mechanisms underlying the pathogenesis of IVDD. Our research may also help direct future investigations into the senescence signaling pathway in IVDD.

NOX4 Regulates NLRP3 by Inhibiting the Ubiquitination of LRRC8A to Promote Ferroptosis in Nucleus Pulposus Cells.

Intervertebral disc degeneration (IDD) is a significant contributor to low back pain, imposing a considerable socioeconomic burden. Ferroptosis, a novel form of cell death driven by iron and characterized by the accumulation of reactive oxygen species (ROS), has been associated with the progression of IDD. Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) has been widely recognized as a pivotal factor promoting ferroptosis across various diseases; however, its precise role in the pathogenesis of IDD remains incompletely understood. Our experimental findings demonstrated a marked upregulation of NOX4 in degenerated cells, accompanied by elevated ROS levels and a diminished mitochondrial membrane potential, indicating the participation of ferroptosis. Furthermore, the expression of the critical regulatory factor GPX4 was reduced, while ACSL4 levels were significantly increased, further corroborating the involvement of ferroptosis. Functional loss and gain experiments revealed that NOX4 overexpression augmented ferroptosis and ROS production while promoting the secretion of inflammatory cytokines. Subsequent studies indicated that the knockdown of NOX4 could reverse tert-butyl hydroperoxide (TBHP)-induced ferroptosis. Mass spectrometry analysis identified leucine-rich repeat-containing 8A (LRRC8A) as an interacting protein of NOX4, and further validation confirmed that they co-regulate Nod-like receptor pyrin domain-3 (NLRP3) activation through their interaction. Utilizing a rat model of intervertebral disc degeneration, we further corroborated the role of NOX4 in IDD. This study provides theoretical support for the potential application of NOX4-targeting drugs in the treatment of IDD.

The impact of uric acid on musculoskeletal diseases: clinical associations and underlying mechanisms

Serum urate (SU) levels are significantly elevated in conditions such as gout, type 2 diabetes (T2D), obesity, and other metabolic syndromes. Recently, due to the high prevalence of hyperuricemia (HUA), numerous clinical connections between SU and musculoskeletal disorders like sarcopenia, osteoarthritis (OA), rheumatoid arthritis (RA), intervertebral disc degeneration (IDD), and osteoporosis (OP) have been identified. This review discusses the mechanisms linking SU to musculoskeletal disorders, as well as the clinical associations of SU with conditions such as sarcopenia, T2D with sarcopenia, McArdle disease, heart failure, gout, OA, IDD, OP and exercise-induced acute kidney injury (EIAKI), offering valuable insights for improved prevention and treatment strategies. Mechanisms linking SU to musculoskeletal disorders include oxidative stress, MSU (monosodium urate) crystal deposition, inflammation, and other factors. In adults, both age and SU levels should be considered for preventing sarcopenia, while gender and SU may directly impact muscle mass in children and adolescents. HUA and gout may be risk factors for OA progression, although some reports suggest otherwise. A U-shaped relationship between SU and IDD has been reported, particularly in Chinese men, indicating lower or higher SU level may be risk factors for IDD. Maintaining SU levels within a certain range may help prevent OP and fractures. Future research, including epidemiological studies and new pathogenesis findings, will further clarify the relationship between musculoskeletal diseases and SU.

Effects of long non-coding RNA KLHL7-AS1 on the proliferation and apoptosis of nucleus pulposus cells under the environment of oxidative stress and its mechanism

Objective: To investigate the effects of long non-coding RNA KLHL7-AS1 (LncRNA KLHL7-AS1) on the proliferation and apoptosis of nucleus pulposus cells under oxidative stress and its mechanisms. Methods: Human nucleus pulposus cells (HUM-iCell-s012) were divided into 4 groups, and unoxidized nucleus pulposus cells were transfected with an empty pcDNA vector (pcDNA-control) to serve as the blank control group. Based on previous studies on oxidative stress-induced nucleus pulposus cell senescence and preliminary experiments, oxidative stress was induced by treating nucleus pulposus cells with 400 μmol/L H2O2. Oxidized nucleus pulposus cells were transfected with pcDNA-control, KLHL7-AS1 interfering RNA (siRNA-KLHL7-AS1), or KLHL7-AS1 overexpression plasmid (pcDNA-KLHL7-AS1), forming the model control group (H2O2+pcDNA-control), the model silencing group (H2O2+siRNA-KLHL7-AS1), and the model overexpression group (H2O2+pcDNA-KLHL7-AS1), respectively. Following these treatments, KLHL7-AS1 expression levels, cell proliferation, cell apoptosis were measured and compared among the groups, and the expression levels of B-cell lymphoma 2 (BCL-2) and BCL-2-associated X protein (BAX) in the groups of cells were compared too (n=3). Results: The expression of KLHL7-AS1 in the model control group was significantly higher than that in the blank control group (7.716±0.851 vs 0.996±0.086, P<0.001). Furthermore, the expression of KLHL7-AS1 in the model overexpression group was markedly higher than that in the model silencing group (19.592±1.747 vs 4.222±0.039, P<0.001). Compared to the blank control group, the model silencing group showed no significant change in cell viability (0.125±0.006 vs 0.127±0.010, P=0.390), an increased apoptosis rate (17.2%±1.7% vs 11.5%±1.0%, P<0.05), elevated BCL-2 protein expression (0.897±0.025 vs 0.730±0.026, P<0.05), and reduced BAX protein expression (0.250±0.030 vs 0.523±0.015, P<0.05). In comparison to the model control group, the model silencing group exhibited increased cell viability (0.125±0.006 vs 0.076±0.008), reduced apoptosis rates (17.2%±1.7% vs 30.7%±2.3%), elevated BCL-2 protein expression (0.730±0.026 vs 0.440±0.036), and decreased BAX protein expression (0.523±0.015 vs 0.723±0.021) (all P<0.001). In comparison to the model silencing group, the model overexpression group showed reduced cell viability (0.125±0.006 vs 0.039±0.006), increased apoptosis rates (43.1%±1.9% vs 17.2%±1.7%), decreased BCL-2 protein expression (0.227±0.021 vs 0.730±0.026), and increased BAX protein expression (1.147±0.035 vs 0.523±0.015) (all P<0.001). Conclusions: Downregulation of KLHL7-AS1 expression promotes the proliferation of nucleus pulposus cells and inhibits their apoptosis, it may involve the regulation of BCL-2 and BAX protein synthesis, potentially delays the progression of intervertebral disc degeneration.

Gallic acid protects intervertebral disc cells from ferroptosis and alleviates intervertebral disc degeneration by regulating key factors of oxidative stress

BackgroundIntervertebral disc degeneration (IDD) is a chronic degenerative disease and one of the main causes of low back pain (LBP). Currently, there is no effective treatment. Ferroptosis is a cell-regulated process that depends on iron deposition and lipid peroxidation. Inhibiting ferroptosis in nucleus pulposus cells is considered a potential strategy for the treatment of IDD. Gallic acid (GA) is naturally present in a variety of plants and has anti-inflammatory, antioxidant and analgesic effects. It has been shown to alleviate ferroptosis. However, the role of GA in IDD ferroptosis remains unclear.MethodsThis study explored the pathological mechanism of GA in IDD in relation to ferroptosis: (1) to identify ferroptosis-related targets for GA treatment of IDD using network pharmacology and molecular docking technology, (2) to evaluate the therapeutic effect of GA in an IDD rat model and changes in ferroptosis-related targets, (3) to investigate the changes of oxidative stress and lipid peroxidation products in NP cells after GA intervention, and (4) to study the changes of ferroptosis-related proteins and iron ions in cells and mitochondria after GA intervention.ResultsExperimental results confirmed that GA can treat IDD by reducing the degradation of extracellular matrix (ECM) and pathological changes in IDD. GA can also mitigate ferroptosis by reducing oxidative stress and lipid peroxidation in rat nucleus pulposus (NP) cells.ConclusionThe alleviation of disc degeneration ferroptosis by GA may be closely associated with the key ferroptosis proteins P53 and NRF2.

End Plate Chondrocyte-Derived Exosomal miR-133a-3p Alleviates Intervertebral Disc Degeneration by Targeting the NF-κB Signaling Pathway through the miR-133a-3p/MAML1 Axis.

Chondrocyte-derived exosomes have shown efficacy in differentiating osteoarthritis-affected cartilage. Intervertebral disc degeneration (IVDD) and osteoarthritis often affect facet joints of the spine and show common epidemiological and pathophysiological characteristics. However, the potential of chondrocyte-derived exosomes for treating IVDD remains unclear. The present study aimed to confirm the effect of end plate chondrocyte-derived exosomes (EPC-Exo) on IVDD and elucidate the underlying mechanism. EPC-Exos were isolated and identified by ultracentrifugation, Western blotting, electron microscopy, and nanoparticle tracking analysis. In the in vitro, EPC-Exo uptake by nucleus pulposus (NP) cells reduced cell death by blocking the nuclear factor-κB (NF-κB) signaling pathway. In the in vivo study, EPC-Exos injected into rat intervertebral discs mitigated lipopolysaccharide-induced IVDD, as revealed by a decreased loss of disc height and improved magnetic resonance imaging findings and histological scores. Bioinformatics and sequencing analyses indicated that EPC-Exos alleviated IVDD through the miR-133a-3p/MAML1 axis. The present study suggests that EPC-Exos reduced IVDD incidence via the miR-133a-3p/MAML1 axis-mediated suppression of NF-κB signaling, which prevented the pyroptosis of NP cells.

Effects of Hsa-miR-4741/LILRB2 on Senescence of Nucleus Pulposus Cells and Their Prognostic Values in Lumbar Disc Herniation

Background The incidence of lumbar disk herniation (LDH) is usually caused by lumbar disk degeneration. Surgery is a common treatment strategy for LDH, but it can recur, resulting in recurrent disk herniation (RDH). Purpose To explore the predictive value of hsa-miR-4741 and LILRB2 in the prognosis of LDH surgery and the mechanism of nucleus pulposus senescence. Method The ROC curves of RDH based on hsa-miR-4741 and LILRB2 were constructed to evaluate their predictive values in the prognosis of LDH surgery. Human nucleus pulposus cells (NPC) was treated by TNF-α to construct a cell senescence model, studying the senescence mechanism. Oxidative stress and senescence markers were detected after overexpression of hsa-miR-4741 and LILRB2 to evaluate their effects on the senescence of NPC. Dual luciferase assay and the transfection of hsa-miR-4741 mimics or inhibitor were used to investigate the targeted regulation of it to LILRB2. Results The combination of hsa-miR-4741 and LILRB2 showed higher accuracy in predicting the outcome of RDH (AUC = 0.9367), compared with a single molecule. Overexpression of hsa-miR-4741 enhanced TNF-α-induced oxidative stress and senescence, while LILRB2 overexpression had the opposite effect. Hsa-miR-4741 mimics attenuated the luciferase activity of NPC transfected with wt-LILRB2 vector and significantly down-regulated LILRB2 expression. In addition, the antioxidant NAC reversed the promotion of hsa-miR-4741 on NPC senescence. Conclusion The combination of hsa-miR-4741 and LILRB2 was a good predictor of LDH prognosis. Hsa-miR-4741 promoted oxidative stress-induced NPC senescence by negatively regulating LILRB2.

Risk factors for progression of nucleus pulposus degeneration in the lumbar intervertebral disc: A retrospective analysis using the disc signal intensity index.

Degenerative disc changes are associated with low back pain and negatively impact quality of life. Disc degeneration process usually starts with nucleus pulposus change. There is uncertainty about the risk factors associated with the progression of disc nucleus degeneration due to the lack of an objective evaluation method. Pfirrmann grade, which assesses the morphological characteristics of a disc on T2-weighted MRI images on a scale of 1 to 5, is one of the most frequently used assessment systems. This method inherently has a degree of subjectivity that may lead to inaccurate and inconsistent grading. A recent study introduced the disc signal intensity index (DSI2) for quantitative assessment of nucleus pulposus degeneration with promising results in identifying of risk factors for progression of disc degeneration. The aim of this study was to investigate the risk factors for the progression of nucleus pulpous degeneration in the lumbar vertebral disc on longitudinal MRI data using DSI2. Retrospective longitudinal study PATIENT SAMPLE: Patients with lumbar MRIs at least three years apart and did not undergo the lumbar spine surgery between both time points were included. Potential contributing factors were collected that included age, biological sex, race, body mass index (BMI), current smoking status, alcohol consumption, history of previous lumbar decompression surgery, and comorbidities such as congestive heart failure (CHF), myocardial infarction, diabetes mellitus, chronic obstructive pulmonary disease, hypertension, and rheumatoid arthritis. Disc nucleus degeneration was assessed using the DSI2 and Pfirrmann grade on T2- weighted MRI. The DSI2 values are based on the mean signal of disc spaces within a circular region of interest (ROI), which was adjusted by the signal intensity of cerebrospinal fluid (CSF) on the midsagittal plane. Three ROIs were set per disc (anterior 1/3, middle, posterior 1/3), and the mean values of all three measurements from L1/2 to L5/S1 disc space were utilized. Discs with complete collapse and no space for ROI selection were excluded. The difference in DSI2 scores between these two time points were compared. Multivariate linear mixed regression analysis was conducted to determine the factors associated with disc degenerative changes. A total of 325 patients and 1439 discs were included in the final analysis. 173 patients (53.2%) were female and the median age of all patients was 60.1 years. The mean (SD) DSI2 score was 0.177 (0.074) for thefirst MRI and 0.184 (0.081) for the second MRI. The Pfirrmann grading for the first MRI timepoint were as follows: 23 discs (1.42%) were Grade 1, 377 discs (23.2%) were Grade 2, 583 discs (35.9%) were Grade 3, 456 discs (28.1%) were Grade 4, and 186 discs (11.5%) were Grade 5. Multivariable linear mixed regression analysis demonstrated that older age (p=0.030) and the presence of congestive heart failure (p<0.001) were significant risk factors for disc nucleus degenerative progression. The present study demonstrated that age and congestive heart failure were risk factors for progression of disc nucleus degeneration. These insights may aid in identifying patients at risk for degenerative lumbar conditions and guide further studies about preventive measures. The DSI2 method offers a promising alternative evaluation method for future disc research.

Ferristatin II protects nucleus pulposus against degeneration through inhibiting ferroptosis and activating HIF-1α pathway mediated mitophagy.

Nucleus pulposus (NP) degeneration represents a significant contributing factor in the pathogenesis of intervertebral disc (IVD) degeneration (IVDD), and is a key underlying mechanism in several lumbar spine pathologies. Nevertheless, the precise mechanisms that govern NP degeneration remain unclear. A significant contributing factor to IVDD has been identified as ferroptosis. Nevertheless, its function in the degeneration of NP remains uncertain. The transferrin receptor inhibitor Ferristatin II (Fer-II) has been demonstrated to possess neuroprotective properties, which are conferred by its ability to suppress ferroptosis. It is therefore crucial to investigate the mechanisms by which Fer-II exerts its protective effects against NP degradation. In order to investigate the protective effects of Fer-II, an IVDD rat model was developed by puncturing the rat tail in vivo. Human NP cells extracted with the aid of tert-butyl hydroperoxide (TBHP) and ferric ammonium citrate (FAC) interventions mimic the IVDD pathological environment in vitro. The present study demonstrates that Fer-II can delay nucleus pulposus degeneration and IVDD by inhibiting ferroptosis. This conclusion was reached through epidemiological studies and in vitro and in vivo experiments. Furthermore, Fer-II was observed to alleviate oxidative stress-induced NP cell degeneration by activating the HIF-1α pathway, enhancing mitophagy, suppressing NP cell ferroptosis. The findings of our study indicate that Fer-II has the potential to safeguard nucleus pulposus cells from degeneration by triggering HIF-1α-mediated mitophagy. The potential of Fer-II as a promising alternative therapeutic option for the management of IVDD is worthy of further investigation.

Preoperative determinants of postoperative expectation fulfillment following elective lumbar spine surgery: an observational study from the Canadian Spine Outcome Research Network (CSORN).

Preoperative patient factors determining expectation fulfillment from elective lumbar surgeries are poorly defined. To identify preoperative factors associated with the levels of expectation fulfillment following elective lumbar spine surgery. This retrospective cohort study used the Canadian Spine Outcome Research Network (CSORN) registry data with participants enrolled between January 2015 and December 2020. The registry prospectively enrolled surgical patients to treat spinal disorders from twenty-three sites. Participating patients completed preoperative and follow-up questionnaires, including information on surgery expectations. Patients recorded their levels of expectation fulfillment on a Likert scale of 1-5, with responses ranging from Completely met (5) to Not applicable (1) in seven expectation dimensions. Consecutive patients with four lumbar conditions (spinal stenosis, disc herniation, degenerative disc disease, or degenerative spondylolisthesis) and those with complete one-year follow-up questionnaires were included. Patients treated for thoracic or cervical pathologies and non-elective lumbar conditions were excluded. A total of 5389 patients who underwent surgery and completed one-year follow-up questionnaires out of 6971 eligible patients were included. Patients' socio-demographics, lifestyle, health status, and clinical factors were examined. The primary outcome was the association between expectation fulfillment and preoperative patient factors. Patient factors were described for the expectation fulfillment categories using descriptive statistics. Bivariable and multivariable associations between patient factors and expectation fulfillment were estimated with ordinal logistic regression models. Point estimates represented as odd ratios, and 95% CIs were reported. The mean age of the participants was 59.5 years, with 49.8% (2683) of them being women. Unmet expectations ranged from 6.7% to 25.7%, with improvement in general physical capacity being the most important expectation fulfilled from surgery for 20% of patients. Factors such as longer symptom duration (OR: 0.74; 95% CI: 0.63-0.86), previous lumbar spine surgery (OR: 0.63; 95% CI: 0.46, 0.89), and reoperations (OR: 0.36; 95% CI: 0.2, 0.63) were associated with higher unmet expectations in the leg pain reduction dimension. Similar results were noted across all other expectation dimensions. Utilizing information on the preoperative factors in presurgical consultations can improve patient satisfaction and expectations from surgery.

PDE4B promotes ferroptosis in nucleus pulposus cells and is involved in intervertebral disc degeneration

Intervertebral Disc degeneration (IDD) is one of the leading causes of disability, and current therapies are ineffective. Phosphodiesterase 4B (PDE4B) plays an essential role in regulating the activation of nuclear factor E2-related factor 2 (Nrf2), while Nrf2 regulates ferroptosis. However, it is still unknown whether PDE4B is involved in the development of IDD. In this study, we explored the role of PDE4B on ferroptosis and Nrf2 in IDD pathogenesis by in vivo and in vitro experiments. The findings suggested that the expressions of PDE4B, ASCL4, and TRFC were significantly upregulated, and the expression of Nrf2 was significantly downregulated in nucleus pulposus (NP) tissues from human IDD patients dependent on IDD degeneration. Overexpression of PDE4B (PDE4B-OE) in NP cells upregulated the expression of ASCL4 and TRFC, and downregulated the expression of Nrf2. Meanwhile, the level of cytokine and oxidative stress were upregulated. Ferroptosis inhibitor Fer-1 or Nrf2 activator dimethyl fumarate (DMF) suppressed the effect of PDE4B-OE, while ferroptosis inducer elastin enhanced the effect of PDE4B-OE. In the IDD rat model, PDE4 inhibitor roflumilast, ferroptosis inhibitor Fer-1, or Nrf2 activator dimethyl fumarate (DMF) delayed IDD pathogenesis. While administration of ferroptosis inducer elastin enhanced IDD pathogenesis. Combination with PDE4B inhibitor and ferroptosis inhibitor Fer-1 significantly synergistic reversed IDD pathogenesis. While combination with PDE4B inhibitor or Nrf2 activator and elastin also decreased the degree of the IDD. The IHC suggested PDE4 inhibitor downregulated the expression of ASCL4 and TRFC. However, the combination effect of the Nrf2 activator was not obvious. Our study suggested that aberrant PDE4B activation in NP tissues induces pathological changes in IDD mediated by ferroptosis, and PDE4 inhibitor reveres the process of IDD by suppressing ferroptosis, and has a synergic effect with ferroptosis inhibitor. So PDE4B inhibition may be a potential therapeutic strategy for IDD.

Backbone breakthroughs: How rodent models are shaping intervertebral disc disease treatment.

Intervertebral disc degeneration (IVDD) is a widespread, disabling condition that significantly contributes to the global burden of musculoskeletal disorders. To better understand its underlying mechanisms and explore potential therapeutic strategies, animal models serve as valuable tools for simulating the complicated pathophysiology of IVDD. Rodent models are extensively used due to their genetic similarities to humans, cost-effectiveness, and rapid attainment of maturity. These models enable the study of specific molecular pathways involved in IVDD, such as inflammation, matrix degradation, tissue repair, and disc microenvironment homeostasis. This review provides a comprehensive overview of the current status of rodent models used in IVDD research, highlighting their advantages, limitations, and contributions to our understanding of the disease. Specifically, we discussed various rodent models, including traumatic (such as needle puncture in the lumbar and coccygeal region, nucleotomy, and annulus fibrosus defect), non-traumatic (including compression models, lumbar spine instability, and bipedalism), chemically induced models (chymopapain, chondroitinase ABC), and genetically modified models. These models offer insights into the severity of IVDD under different conditions, such as trauma, aging, and genetics. In conclusion, rodent models remain indispensable tools for advancing our understanding of IVDD mechanisms and therapeutic interventions. Carefully selecting animal species and models can provide valuable insights that guide future clinical research and treatment approaches. Our review aims to leverage these models to identify therapeutic targets and strategies that may ultimately reduce the impact of IVDD on human health. PERSPECTIVE: This review describes the role of rodent models in IVDD, highlighting their utility in unraveling disease mechanisms and evaluating therapeutics. By replicating the complex molecular pathways and conditions of disc disease, like trauma, aging, and genetics, these models aid in identifying future advancements in managing lower back pain.

Fuzi decoction ameliorates intervertebral disc degeneration through ferroptosis modulation by suppressing NF-κB pathway.

Intervertebral disc degeneration (IVDD) is a complex condition that necessitates the development of novel therapeutic strategies. The objective of this study was to investigate the therapeutic potential of Fuzi decoction (FZD) in the treatment of IVDD by examining its bioactive components, target genes, molecular interactions, pathways, and therapeutic efficacy. Bioactive ingredients with an oral bioavailability (OB) of≥30% and drug likeness (DL) of≥0.18 were identified using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. Target genes associated with IVDD were retrieved from various databases, and a Venn diagram was employed to determine the common targets between IVDD and FZD. Subsequent network analyses, including ingredient-target-disease networks and protein-protein interaction (PPI) networks, were constructed. Functional enrichment analyses, such as Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), were conducted to delineate the biological processes, pathways, and potential mechanisms. Molecular docking was utilized to validate the interactions between FZD ingredients and target genes. In vitro assays using nucleus pulposus cells (NPCs) evaluated the effects of FZD-containing serum (FCS) on extracellular matrix (ECM) degradation, ferroptosis, and NF-κB pathway modulation. Additionally, rat models were used to confirm the therapeutic effects of FZD on IVDD. FZD was found to contain 77 bioactive ingredients and 108 related targets, with 101 common targets identified between IVDD and FZD. Network analyses pinpointed key ingredients and targets, with a particular focus on PTGS2 and IL1B as central to IVDD. Enrichment analyses revealed pathways related to reactive oxygen species and NF-κB signaling. Molecular docking confirmed robust interactions between core ingredients and target proteins. Pharmacological findings were substantiated by in vitro and in vivo experiments, demonstrating that FCS alleviated IL-1β-induced ECM degradation and ferroptosis by inhibiting the NF-κB pathway in NPCs. FZD demonstrates efficacy in alleviating IVDD by regulating ECM degradation and ferroptosis through the suppression of the NF-κB signaling pathway. These findings suggest that FZD may be a promising therapeutic agent for the treatment of IVDD, offering insights into its multifaceted mechanisms and molecular interactions for potential clinical application.