Pharmacological Treatment of Degenerative Cervical Myelopathy: A Critical Review of Current Evidence.

Degenerative cervical myelopathy (DCM) is the leading cause of spinal cord dysfunction in adults, representing substantial morbidity and significant financial and resource burdens. Typically, patients with progressive DCM will eventually receive surgical treatment. Nonetheless, despite advancements in pharmacotherapeutics, evidence for pharmacological therapy remains limited. Health professionals from various fields would find interest in pharmacological agents that could benefit patients with mild DCM or enhance surgical outcomes. This review aims to consolidate all clinical and experimental evidence on the pharmacological treatment of DCM. We conducted a comprehensive narrative review that presents all pharmacological agents that have been investigated for DCM treatment in both humans and animal models. Riluzole exhibits effectiveness solely in rat models, but not in treating mild DCM in humans. Cerebrolysin emerges as a potential neuroprotective agent for myelopathy in animals but had contradictory results in clinical trials. Limaprost alfadex demonstrates motor function improvement in animal models and exhibits promising outcomes in a small clinical trial. Glucocorticoids not only fail to provide clinical benefits but may also lead to adverse events. Cilostazol, anti-Fas ligand antibody, and Jingshu Keli display promise in animal studies, while erythropoietin, granulocyte colony-stimulating factor and limaprost alfadex exhibit potential in both animal and human research. Existing evidence mainly rests on weak clinical data and animal experimentation. Current pharmacological efforts target ion channels, stem cell differentiation, inflammatory, vascular, and apoptotic pathways. The inherent nature and pathogenesis of DCM offer substantial prospects for developing neurodegenerative or neuroprotective therapies capable of altering disease progression, potentially delaying surgical intervention, and optimizing outcomes for those undergoing surgical decompression.

POSTN knockdown suppresses IL-1ß-induced inflammation and apoptosis of nucleus pulposus cells via inhibiting the NF-κB pathway and alleviates intervertebral disc degeneration.

The aim of this study is to investigate the effects of POSTN on IL-1ß induced inflammation, apoptosis, NF-κB pathway and intervertebral disc degeneration (IVDD) in Nucleus pulposus (NP) cells (NPCs). NP tissue samples with different Pfirrmann grades were collected from patients with different degrees of IVDD. Western blot and immunohistochemical staining were used to compare the expression of POSTN protein in NP tissues. Using the IL-1ß-induced IVDD model, NPCs were transfected with lentivirus-coated si-POSTN to down-regulate the expression of POSTN and treated with CU-T12-9 to evaluate the involvement of NF-κB pathway. Western blot, immunofluorescence, and TUNEL staining were used to detect the expression changes of inflammation, apoptosis and NF-κB pathway-related proteins in NPCs. To investigate the role of POSTN in vivo, a rat IVDD model was established by needle puncture of the intervertebral disc. Rats were injected with lentivirus-coated si-POSTN, and H&E staining and immunohistochemical staining were performed. POSTN expression is positively correlated with the severity of IVDD in human. POSTN expression was significantly increased in the IL-1ß-induced NPCs degeneration model. Downregulation of POSTN protects NPCs from IL-1ß-induced inflammation and apoptosis. CU-T12-9 treatment reversed the protective effect of si-POSTN on NPCs. Furthermore, lentivirus-coated si-POSTN injection partially reversed NP tissue damage in the IVDD model in vivo. POSTN knockdown reduces inflammation and apoptosis of NPCs by inhibiting NF-κB pathway, and ultimately prevents IVDD. Therefore, POSTN may be an effective target for the treatment of IVDD.

The Differences on the Fatty Infiltration of Paraspinal Muscles between Single- and Multiple-level Intervertebral Disc Degeneration in Patients with Lumbar Disc Herniation.

OBJECTIVE: Multiple-level Intervertebral disc degeneration (IDD) in patients with lumbar disc herniation (LDH) is related to postoperative re-herniation and low back pain. Although many investigators believed that there is an interdependence between paraspinal muscles degeneration and IDD, few studies focused on the fatty infiltration of paraspinal muscles on single- and multiple-level IDD in patients with LDH. This study aims to investigate the difference on the fatty infiltration of paraspinal muscles between single- and multiple-levels IDD in patients with LDH. and to explore in patients with LDH whether fatty infiltration is a potential risk factor for multiple-level IDD. METHODS: This study was conducted as a retrospective observational analysis of 82 patients with LDH from January 1, 2020 to December 30, 2020 in our hospital were enrolled. Twenty-seven cases had single-level IDD (Group A), and 55 cases had multiple-level IDD (Group B). We measured the mean computed tomography (CT) density value of the paraspinal muscles, including multifidus (MF), erector spinae (ES) and psoas muscle (PM) at each disc from L1 to S1. Subgroups were set to further analyze the odds ratio (OR) of fatty infiltration of paraspinal muscles in different sex and BMI groups. We measured sagittal angles and analyzed the relationships between these angles and IDD. Finally, we use logistic regression, adjusted for other confounding factors, to investigate whether fatty infiltration is an independent risk factor for multi-level IDD. RESULTS: The average age in multi-level IDD (51.40 ± 15.47 years) was significantly higher than single-level IDD (33.37 ± 7.10 years). The mean CT density value of MF, ES and PM in single-level IDD was significantly higher than multi-level IDD (all ps < 0.001). There was no significant difference of the mean value of angles between the two groups. No matter being fat (body mass index [BMI] > 24.0 kg/m2) or normal, patients with low mean muscle CT density value of MF and ES are significantly easier to suffer from multiple-level IDD. In the pure model, the average CT density value of the MF, ES and PM is all significantly associated with the occurrence of multi-IDD. However, after adjusting for various confounding factors, only the OR of the average CT density value for MF and ES remains statistically significant (OR = 0.810, 0.834, respectively). CONCLUSIONS: In patients with LDH, patients with multiple-level IDD have more severe fatty infiltration of MF and ES than those with single-level IDD. Fatty infiltration of MF and ES are independent risk factors for multiple-level IDD in LDH patients.

Needle-scalpel therapy inhibits the apoptosis of nucleus pulposus cells via the SDF-1/CXCR4 axis in a rat degenerative cervical intervertebral disc model.

As a common disease, cervical spondylosis (CS) results from the degeneration of the cervical intervertebral disc. However, there are still no effective clinical strategies for the treatment of this disease. Needle-scalpel (Ns), a therapy guided by traditional Chinese medicine theory, alleviates intervertebral disc degradation and is widely used in the clinic to treat CS. Stromal cell-derived factor-1 (SDF-1) and its receptor CXC receptor 4 (CXCR4) in nucleus pulposus cells play an important role in CS onset and development. This study aimed to explore whether Ns can relieve pain and regulate the SDF-1/CXCR4 axis in nucleus pulposus cells to inhibit apoptosis, thereby delaying cervical intervertebral disc degradation in a rat model of CS. It was found that the Ns-treated groups exhibited higher mechanical allodynia scores than the model group, and H&E staining, MRI, and scanning electron microscopy revealed that Ns therapy inhibited intervertebral disc degeneration. Additionally, Ns therapy significantly inhibited increases in the RNA and protein expression levels of SDF-1 and CXCR4. Furthermore, these treatments alleviated the apoptosis of nucleus pulposus cells, which manifested as a decline in the proportion of apoptotic nucleus pulposus cells and inhibition of the decrease in the levels of Bcl-2/Bax. These findings indicated that Ns mitigated CS-induced pain, inhibited the apoptosis of nucleus pulposus cells, and alleviated intervertebral disc degeneration in CS rats. These effects may be mediated by specifically regulating the SDF-1/CXCR4 signaling axis. Based on these findings, we conclude that Ns might serve as a promising therapy for the treatment of CS.

Correlation between degeneration of cervical intervertebral disc and degeneration of paravertebral muscle.

Objective: To investigate the relationship between degeneration of cervical intervertebral disc and degeneration of paravertebral muscles[multifidus (MF), cervical semispinalis (SCer), semispinalis capitis (SCap) and splenius capitis (SPL)]. Methods: 82 patients with chronic neck pain were randomly selected, including 43 males and 39 females, with 50.73 0.7.51 years old. All patients were scanned by 3.0T MRI Philips Ingenia performed conventional MRI sequence scanning and fat measurement sequence mDIXON-Quant scanning of cervical. Fat infiltration (FI) and cross-sectional area (CSA) of cervical paravertebral muscle (MF, SCer, SCap and SPL) at central level of C5-6 disc were measured by Philips 3.0T MRI image post-processing workstation. According to Pfirrmann grading system, there was no grade I in the included cases. The number of grade IIr IV cases were n=16, 40, 19 and 7 respectively. CSA and FI of cervical paravertebral muscles were compared with t test or one-way ANOVA, Spearman correlation analysis was used to evaluate the correlation between age, disc degeneration, and CSA, FI of cervical paravertebral muscles, and multiple linear regression analysis was used to analyze the independent influencing factors of CSA and FI. Results: CSA of cervical paravertebral muscles in male patients was significantly higher than that in female patients (all P<0.001), but there was no significant difference in FI (all P>0.05). Age was weakly correlated with CSA of MF+SCer, moderately correlated with CSA of SCap and SPL (r=-0.256, -0.355 and -0.361, P<0.05), weakly correlated with FI of SCap and SPL (r= 0.182 and 0.264, P<0.001), moderately correlated with FI of MF+SCer (r=0.408, P<0.001). There were significant differences in FI with disc degeneration (P<0.001, P=0.028 and P=0.005). Further correlation analysis showed that disc degeneration was strongly correlated with FI of MF+SCer (r=0.629, P<0.001), and moderately correlated with FI of SCap and SPL (r=0.363, P=0.001; r=0.345, P=0.002). Multiple linear regression analysis showed that sex and age were the influencing factors of CSA of SCap and SPL, sex was the independent influencing factor of CSA of MF+SCer, and disc degeneration was the independent influencing factor of FI. Conclusions: Age is negatively correlated with CSA and positively correlated with FI. Disc degeneration was correlated with FI of paravertebral muscles, especially with FI of MF and SCer. Sex and age were the influencing factors of CSA, while disc degeneration was the independent influencing factor of FI.

Intervertebral disc degeneration produced by vertebral body fracture associated with microcirculation disruption of the sub-endplate.

BACKGROUND: Among the causes of the progression of intervertebral disc (IVD) degeneration (IDD) is the loss of nutrient intake to the IVD through the microcirculation disruption of the sub-endplate. Also, the vertebral body fracture intervenes in degenerating the adjacent IVD. This research aimed to create an animal model of IDD using these two strategies. METHODS: 30 male Sprague-Dawley rats were split into 3 groups: a control group, a middle vertebral body injury (MI) associated with ethanol injection (MI+EtOH) group, and an MI associated with phosphate-buffered saline injection (MI+PBS) group. A vertebral body fracture with or without endplate injection of ethanol was generated by either drilling a hole in the center of a caudal rat vertebral body to form a fracture with an unabated endplate or drilling a hole in the center of a rat coccygeal vertebral body with endplate injection of ethanol to establish a vertebral body fracture with endplate damage. X-ray, macroscopic, histologic, and biochemical evaluations were utilized to assess IDD at weeks 3 and 6. RESULTS: According to X-ray findings, the MI+EtOH group demonstrated a significant decrease in intervertebral space height over time in comparison to the 2 other groups. The water content also was significantly decreased. Macroscopic and histological analysis demonstrated progressive degenerative changes in the IVD of the MI+EtOH group. CONCLUSION: The caudal vertebra fracture with ethanol injection is more likely to induce degeneration of adjacent IVD. This model effectively repreduced IDD, which may serve as a theoretical basis for future clinical intervention for IDD.

Exosomes derived from human urine-derived stem cells ameliorate IL-1ß-induced intervertebral disk degeneration.

BACKGROUND: Human intervertebral disk degeneration (IVDD) is a sophisticated degenerative pathological process. A key cause of IVDD progression is nucleus pulposus cell (NPC) degeneration, which contributes to excessive endoplasmic reticulum stress in the intervertebral disk. However, the mechanisms underlying IVDD and NPC degeneration remain unclear. METHODS: We used interleukin (IL)-1ß stimulation to establish an NPC-degenerated IVDD model and investigated whether human urine-derived stem cell (USC) exosomes could prevent IL-1ß-induced NPC degeneration using western blotting, quantitative real-time polymerase chain reaction, flow cytometry, and transcriptome sequencing techniques. RESULTS: We successfully extracted and identified USCs and exosomes from human urine. IL-1ß substantially downregulated NPC viability and induced NPC degeneration while modulating the expression of SOX-9, collagen II, and aggrecan. Exosomes from USCs could rescue IL-1ß-induced NPC degeneration and restore the expression levels of SOX-9, collagen II, and aggrecan. CONCLUSIONS: USC-derived exosomes can prevent NPCs from degeneration following IL-1ß stimulation. This finding can aid the development of a potential treatment strategy for IVDD.

Rescue of nucleus pulposus cells from an oxidative stress microenvironment via glutathione-derived carbon dots to alleviate intervertebral disc degeneration.

The senescence of nucleus pulposus (NP) cells (NPCs), which is induced by the anomalous accumulation of reactive oxygen species (ROS), is a major cause of intervertebral disc degeneration (IVDD). In this research, glutathione-doped carbon dots (GSH-CDs), which are novel carbon dot antioxidant nanozymes, were successfully constructed to remove large amounts of ROS for the maintenance of NP tissue at the physical redox level. After significantly scavenging endogenous ROS via exerting antioxidant activities, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and total antioxidant capacity, GSH-CDs with good biocompatibility have been demonstrated to effectively improve mitochondrial dysfunction and rescue NPCs from senescence, catabolism, and inflammatory factors in vivo and in vitro. In vivo imaging data and histomorphological indicators, such as the disc height index (DHI) and Pfirrmann grade, demonstrated prominent improvements in the progression of IVDD after the topical application of GSH-CDs. In summary, this study investigated the GSH-CDs nanozyme, which possesses excellent potential to inhibit the senescence of NPCs with mitochondrial lesions induced by the excessive accumulation of ROS and improve the progression of IVDD, providing potential therapeutic options for clinical treatment.

Spotlight on necroptosis: Role in pathogenesis and therapeutic potential of intervertebral disc degeneration.

Intervertebral disc degeneration (IDD) is the leading cause of low back pain, which is one of the major factors leading to disability and severe economic burden. Necroptosis is an important form of programmed cell death (PCD), a highly regulated caspase-independent type of cell death that is regulated by receptor-interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like protein (MLKL)-mediated, play a key role in the pathophysiology of various inflammatory, infectious and degenerative diseases. Recent studies have shown that necroptosis plays an important role in the occurrence and development of IDD. In this review, we provide an overview of the initiation and execution of necroptosis and explore in depth its potential mechanisms of action in IDD. The analysis focuses on the connection between NP cell necroptosis and mitochondrial dysfunction-oxidative stress pathway, inflammation, endoplasmic reticulum stress, apoptosis, and autophagy. Finally, we evaluated the possibility of treating IDD by inhibiting necroptosis, and believed that targeting necroptosis may be a new strategy to alleviate the symptoms of IDD.

IL-1ra loaded chondroitin sulfate-functionalized microspheres for minimally invasive treatment of intervertebral disc degeneration.

Presently, the clinical treatment of intervertebral disc degeneration (IVDD) remains challenging, but the strategy of simultaneously overcoming the overactive inflammation and restoring the anabolic/catabolic balance of the extracellular matrix (ECM) in the nucleus pulposus (NP) has become an effective way to alleviate IVDD. IL-1ra, a natural antagonist against IL-1ß, can mitigate inflammation and promote regeneration in IVDD. Chondroitin sulfate (CS), an important component of the NP, can promote ECM synthesis and delay IVDD. Thus, these were chosen and integrated into functionalized microspheres to achieve their synergistic effects. First, CS-functionalized microspheres (GelMA-CS) with porous microstructure, good monodispersion, and about 200 µm diameter were efficiently and productively fabricated using microfluidic technology. After lyophilization, the microspheres with good local injection and tissue retention served as the loading platform for IL-1ra and achieved sustained release. In in vitro experiments, the IL-1ra-loaded microspheres exhibited good cytocompatibility and efficacy in inhibiting the inflammatory response of NP cells induced by lipopolysaccharide (LPS) and promoting the secretion of ECM. In in vivo experiments, the microspheres showed good histocompatibility, and local, minimally invasive injection of the IL-1ra-loaded microspheres could reduce inflammation, maintain the height of the intervertebral disc (IVD) and the water content of NP close to about 70 % in the sham group, and retain the integrated IVD structure. In summary, the GelMA-CS microspheres served as an effective loading platform for IL-1ra, eliminated inflammation through the controlled release of IL-1ra, and promoted ECM synthesis via CS to delay IVDD, thereby providing a promising intervention strategy for IVDD. STATEMENT OF SIGNIFICANCE: The strategy of simultaneously overcoming the overactive inflammation and restoring the anabolic/catabolic balance of the extracellular matrix (ECM) in nucleus pulposus (NP) has shown great potential prospects for alleviating intervertebral disc degeneration (IVDD). From the perspective of clinical translation, this study developed chondroitin sulfate functionalized microspheres to act as the effective delivery platform of IL-1ra, a natural antagonist of interleukin-1ß. The IL-1ra loading microspheres (GelMA-CS-IL-1ra) showed good biocompatibility, good injection with tissue retention, and synergistic effects of inhibiting the inflammatory response induced by lipopolysaccharide and promoting the secretion of ECM in NPCs. In vivo, they also showed the beneficial effect of reducing the inflammatory response, maintaining the height of the intervertebral disc and the water content of the NP, and preserving the integrity of the intervertebral disc structure after only one injection. All demonstrated that the GelMA-CS-IL-1ra microspheres would have great promise for the minimally invasive treatment of IVDD.

Investigating the characteristics of mild intervertebral disc degeneration at various age stages using single-cell genomics.

Introduction: Intervertebral disc degeneration often occurs in the elderly population, but in recent years, there has been an increasing incidence of disc degeneration in younger individuals, primarily with mild degeneration. Methods: In order to explore the underlying mechanisms of disc degeneration in both young and aging individuals, we collected four types of nucleus pulposus (NP) single-cell sequencing samples for analysis based on Pfirrmann grading: normal-young (NY) (Grade I), normal-old (NO) (Grade I), mild degenerative-young (MY) (Grade II-III), and mild degenerative-old (MO) (Grade II-III). Results: We found that most NP cells in NO and MY samples exhibited oxidative stress, which may be important pathogenic factors in NO and MY groups. On the other hand, NP cells in MO group exhibited endoplasmic reticulum stress. In terms of inflammation, myeloid cells were mainly present in the degenerative group, with the MY group showing a stronger immune response compared to the MO group. Interestingly, dendritic cells in the myeloid lineage played a critical role in the process of mild degeneration. Discussion: Our study investigated the molecular mechanisms of intervertebral disc degeneration from an age perspective, providing insights for improving treatment strategies for patients with disc degeneration at different age groups.

Advances in the interaction between lumbar intervertebral disc degeneration and fat infiltration of paraspinal muscles: critical summarization, classification, and perspectives.

More than 619 million people in the world suffer from low back pain (LBP). As two potential inducers of LBP, intervertebral disc degeneration (IVDD) and fat infiltration of paraspinal muscles (PSMs) have attracted extensive attention in recent years. So far, only one review has been presented to summarize their relationship and relevant mechanisms. Nevertheless, it has several noticeable drawbacks, such as incomplete categorization and discussion, lack of practical proposals, etc. Consequently, this paper aims to systematically summarize and classify the interaction between IVDD and fat infiltration of PSMs, thus providing a one-stop search handbook for future studies. As a result, four mechanisms of IVDD leading to fat infiltration of PSMs and three mechanisms of fat infiltration in PSMs causing IVDD are thoroughly analyzed and summarized. The typical reseaches are tabulated and evaluated from four aspects, i.e., methods, conclusions, benefits, and drawbacks. We find that IVDD and fat infiltration of PSMs is a vicious cycle that can promote the occurrence and development of each other, ultimately leading to LBP and disability. Finally, eight perspectives are proposed for future in-depth research.

Progress in the Application of Hydrogels in Intervertebral Disc Repair: A Comprehensive Review.

PURPOSE OF REVIEW: Intervertebral disc degeneration (IVDD) is a common orthopaedic disease and an important cause of lower back pain, which seriously affects the work and life of patients and causes a large economic burden to society. The traditional treatment of IVDD mainly involves early pain relief and late surgical intervention, but it cannot reverse the pathological course of IVDD. Current studies suggest that IVDD is related to the imbalance between the anabolic and catabolic functions of the extracellular matrix (ECM). Anti-inflammatory drugs, bioactive substances, and stem cells have all been shown to improve ECM, but traditional injection methods face short half-life and leakage problems. RECENT FINDINGS: The good biocompatibility and slow-release function of polymer hydrogels are being noticed and explored to combine with drugs or bioactive substances to treat IVDD. This paper introduces the pathophysiological mechanism of IVDD, and discusses the advantages, disadvantages and development prospects of hydrogels for the treatment of IVDD, so as to provide guidance for future breakthroughs in the treatment of IVDD.

Causal relationship between bone mineral density and intervertebral disc degeneration: a univariate and multivariable mendelian randomization study.

BACKGROUND: Although previous studies have suggested a possible association between bone mineral density (BMD) and intervertebral disc degeneration (IDD), the causal relationship between them remains unclear. Evidence from accumulating studies indicates that they might mutually influence one another. However, observational studies may be affected by potential confounders. Meanwhile, Mendelian randomization (MR) study can overcome these confounders to assess causality. OBJECTIVES: This Mendelian randomization (MR) study aimed to explore the causal effect of bone mineral density (BMD) on intervertebral disc degeneration (IDD). METHODS: Summary data from genome-wide association studies of bone mineral density (BMD) and IDD (the FinnGen biobank) have been acquired. The inverse variance weighted (IVW) method was utilized as the primary MR analysis approach. Weighted median, MR-Egger regression, weighted mode, and simple mode were used as supplements. The Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) and MR-Egger regression were performed to assess horizontal pleiotropy. Cochran's Q test evaluated heterogeneity. Leave-one-out sensitivity analysis was further conducted to determine the reliability of the causal relationship. Multivariate MR (MVMR) analyses used multivariable inverse variance-weighted methods to individually and jointly adjust for four potential confounders, body mass index (BMI), Type2 diabetes, hyperthyroidism and smoking. A reverse MR analysis was conducted to assess potential reverse causation. RESULTS: In the univariate MR analysis, femoral neck bone mineral density (FNBMD), heel bone mineral density (eBMD), lumbar spine bone mineral density (LSBMD), and total body bone mineral density (TB BMD) had a direct causal effect on intervertebral disc degeneration (IDD) [FNBMD-related analysis: OR(95%CI) = 1.17 (1.04 to 1.31), p = 0.008, eBMD-related analysis: OR(95%CI) = 1.06 (1.01 to 1.12), p = 0.028, LSBMD-related analysis: OR(95%CI) = 1.20 (1.10 to 1.31), p = 3.38E-7,TB BMD-related analysis: OR(95%CI) = 1.20 (1.12 to 1.29), p = 1.0E-8]. In the MVMR analysis, it was revealed that, even after controlling for confounding factors, heel bone mineral density (eBMD), lumbar spine bone mineral density (LSBMD), and total body bone mineral density (TB BMD) still maintained an independent and significant causal association with IDD(Adjusting for heel bone mineral density: beta = 0.073, OR95% CI = 1.08(1.02 to 1.14), P = 0.013; Adjusting for lumbar spine bone mineral density: beta = 0.11, OR(95%CI) = 1.12(1.02 to 1.23), P = 0.03; Adjusting for total body bone mineral density: beta = 0.139, OR95% CI = 1.15(1.06 to 1.24), P = 5.53E - 5). In the reverse analysis, no evidence was found to suggest that IDD has an impact on BMD. CONCLUSIONS: The findings from our univariate and multivariable Mendelian randomization analysis establish a substantial positive causal association between BMD and IDD, indicating that higher bone mineral density may be a significant risk factor for intervertebral disc degeneration. Notably, no causal effect of IDD on these four measures of bone mineral density was observed. Further research is required to elucidate the underlying mechanisms governing this causal relationship.

Hypoxia-Preconditioned BMSC-Derived Exosomes Induce Mitophagy via the BNIP3-ANAX2 Axis to Alleviate Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IVDD) is a chronic degenerative disease involving the aging and loss of proliferative capacity of nucleus pulposus cells (NPCs), processes heavily dependent on mitochondrial dynamics and autophagic flux. This study finds that the absence of BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) is associated with senescence-related NPC degeneration, disrupting mitochondrial quality control. Bone marrow mesenchymal stem cells (BMSCs) have multidirectional differentiation potential and produce extracellular vesicles containing cellular activators. Therefore, in this study, BMSCs are induced under hypoxic stimulation to deliver BNIP3-rich extracellular vesicles to NPCs, thereby alleviating aging-associated mitochondrial autophagic flux, promoting damaged mitochondrial clearance, and restoring mitochondrial quality control. Mechanistically, BNIP3 is shown to interact with the membrane-bound protein annexin A2 (ANXA2), enabling the liberation of the transcription factor EB (TFEB) from the ANXA2-TFEB complex, promoting TFEB nuclear translocation, and regulating autophagy and lysosomal gene activation. Furthermore, a rat model of IVDD is established and verified the in vivo efficacy of the exosomes in repairing disc injuries, delaying NPC aging, and promoting extracellular matrix (ECM) synthesis. In summary, hypoxia-induced BMSC exosomes deliver BNIP3-rich vesicles to alleviate disc degeneration by activating the mitochondrial BNIP3/ANXA2/TFEB axis, providing a new target for IVDD treatment.

Impact of Preoperative Intervertebral Disc Degeneration on Patient-Reported Outcome Measures After Lumbar Fusion.

OBJECTIVE: The Pfirrmann scoring system classifies lumbosacral disc degeneration based on MRI signal intensity. The relationship between pre-existing disc degeneration and PROMs after one-level lumbar fusion is not well documented. The purpose of this study was to investigate the relationship between the severity of preoperative intervertebral disc degeneration and pre- and postoperative patient-reported outcome measures (PROMs) in patients undergoing one-level lumbar fusion. METHODS: All adult patients underwent posterior lumbar decompression and fusion (PLDF) or transforaminal lumbar interbody fusion (TLIF) between 2014-2022 were included. Patient demographics, and comorbidities were extracted from medical records. Lumbar intervertebral discs on sagittal MRI T2-weighted images were assessed by two independent graders utilizing Pfirrmann criteria. Grades I-III were categorized as low-grade disc degeneration, while IV-V were considered high-grade. Multivariable linear regression assessed the impact of disc degeneration on PROMS. RESULTS: A total of 150 patients were included, of which, 69 (46%) had low grade disc degeneration, while 81 (54%) had high grade degeneration. Patients with high-grade degeneration had increased preoperative VAS-Leg scores (6.10 vs. 4.54, p=0.005) and displayed greater one-year postoperative improvements in VAS-Back scores (-2.11 vs -0.66, p=0.002). Multivariable regression demonstrated Pfirrmann scores as independent predictors for both preoperative VAS-Leg scores (p=0.004) and postoperative VAS-Back improvement (p=0.005). CONCLUSIONS: In patients undergoing one-level lumbar fusion, higher Pfirmann scores were associated with increased preoperative leg pain and greater one-year postoperative improvement in back pain. Further studies into the relationship of pre-operative disc degeneration and their impact on postoperative outcomes may help guide clinical decision making and patient expectations.

Research progress on long non­coding RNAs in non­infectious spinal diseases (Review).

Spinal diseases, including intervertebral disc degeneration (IDD), ankylosing spondylitis, spinal cord injury and other non­infectious spinal diseases, severely affect the quality of life of patients. Current treatments for IDD and other spinal diseases can only relieve symptoms and do not completely cure the disease. Therefore, there is an urgent need to explore the causes of these diseases and develop new treatment approaches. Long non­coding RNA (lncRNA), a form of non­coding RNA, is abundant in diverse sources, has numerous functions, and plays an important role in the occurrence and development of spinal diseases such as IDD. However, the mechanism of action of lncRNAs has not been fully elucidated, and significant challenges remain in the use of lncRNAs as new therapeutic targets. The present article reviews the sources, classification and functions of lncRNAs, and introduces the role of lncRNAs in spinal diseases, such as IDD, and their therapeutic potential.

Exploring causal correlations between inflammatory cytokines and intervertebral disc degeneration: A Mendelian randomization.

Background: Inflammatory cytokines have been reported to be related to intervertebral disc degeneration (IVDD) in several previous studies. However, it remains unclear about the causal relationship between inflammatory cytokines and IVDD. This study employs Mendelian randomization (MR) to analyze the causal link between inflammatory cytokines and the risk of IVDD. Method: We used genetic variants associated with inflammatory cytokines from a meta-analysis of genome-wide association study (GWAS) in 8293 Finns as instrumental variables and IVDD data were sourced from the FinnGen consortium. The main analytical approach utilized Inverse-Variance Weighting (IVW) with random effects to assess the causal relationship. Additionally, complementary methods such as MR-Egger, weighted median, simple mode, weighted mode, and MR pleiotropy residual sum and outlier were employed to enhance the robustness of the final results. Result: We found interferon-gamma (IFN-γ, p = 2.14 × 10-6, OR = 0.870, 95% CI = 0.821-0.921), interleukin-1 beta (IL-1b, p = 0.012, OR = 0.951, 95% CI = 0.914-0.989), interleukin-4 (IL-4, p = 0.034, OR = 0.946, 95% CI = 0.899-0.996), interleukin-18 (IL-18, p = 0.028, OR = 0.964, 95% CI = 0.934-0.996), granulocyte colony-stimulating factor (GCSF, p = 0.010, OR = 0.919, 95% CI = 0.861-0.980), and Stromal cell-derived factor 1a (SDF1a, p = 0.014, OR = 1.072, 95% CI = 1.014-1.134) were causally associated with risk of IVDD. Conclusion: Our MR analyses found a potential causal relationship between six inflammation cytokines (IFN-γ, IL-1b, IL-4, IL-18, SDF1a, and GCSF) and altered IVDD risk.

Metformin prevents the onset and progression of intervertebral disc degeneration: New insights and potential mechanisms (Review).

Metformin has been the go­to medical treatment for addressing type 2 diabetes mellitus (T2DM) as a frontline oral antidiabetic. Obesity, cancer and bone deterioration are linked to T2DM, which is considered a metabolic illness. Numerous diseases associated with T2DM, such as tumours, cardiovascular disease and bone deterioration, may be treated with metformin. Intervertebral disc degeneration (IVDD) is distinguished by degeneration of the spinal disc, accompanied by the gradual depletion of proteoglycans and water in the nucleus pulposus (NP) of the IVD, resulting in lower back pain. The therapeutic effect of metformin on IVDD has also attracted much attention. By stimulating AMP­activated kinase, metformin could enhance autophagy and suppress cell senescence, apoptosis and inflammation, thus effectively delaying IVDD. The present review aimed to systematically explain the development of IVDD and mechanism of metformin in the treatment and prevention of IVDD to provide a reference for the clinical application of metformin as adjuvant therapy in the treatment of IVDD.

Index-level fusion and adjacent segment disease following dynamic stabilization for lumbar degenerative disc disease: illustrative case.

BACKGROUND: Dynesys dynamic stabilization (DDS) is an alternative to surgical fusion for the operative management of degenerative lumbar spondylosis. Compared to rigid instrumentation and fusion, DDS is purported to preserve a higher degree of spinal range of motion and reduce the risk of developing adjacent segment disease (ASD). OBSERVATIONS: A 60-year-old female presented with severe back pain and bilateral leg pain, which had progressed over the prior 4 years. Nine years earlier, she had undergone DDS system implantation at L5-S1 for lumbar stenosis and spondylosis. Repeat imaging revealed an unintended fusion at the index level (L5-S1) and ASD causing severe lateral recess stenosis at L4-5. She underwent DDS system removal, decompression at L4-5, and extension of the fusion to L4. LESSONS: Although DDS has been marketed as a motion-preserving system that avoids fusion and reduces the risk of ASD, unintended index-level fusion and ASD can still occur after DDS system surgery. These potential complications should be assessed when determining the optimal primary surgical treatment for patients with lumbar degenerative disc disease. https://thejns.org/doi/10.3171/CASE24179.