Dynamics of CD44+ bovine nucleus pulposus cells with inflammation.

Intervertebral Disc (IVD) degeneration has been associated with a chronic inflammatory response, but knowledge on the contribution of distinct IVD cells, namely CD44, to the progression of IVD degeneration remains elusive. Here, bovine nucleus pulposus (NP) CD44 cells were sorted and compared by gene expression and proteomics with the negative counterpart. NP cells were then stimulated with IL-1b (10 ng/ml) and dynamics of CD44 gene and protein expression was analyzed upon pro-inflammatory treatment. The results emphasize that CD44 has a multidimensional functional role in IVD metabolism, ECM synthesis and production of neuropermissive factors. CD44 widespread expression in NP was partially associated with CD14 and CD45, resulting in the identification of distinct cell subsets. In conclusion, this study points out CD44 and CD44-based cell subsets as relevant targets in the modulation of the IVD pro-inflammatory/degenerative cascade.

Role of Galectin-3 in intervertebral disc degeneration: an experimental study.

BACKGROUND: This study investigated the role of Galectin-3 in the degeneration of intervertebral disc cartilage. METHODS: The patients who underwent lumbar spine surgery due to degenerative disc disease were recruited and divided into Modic I, Modic II, and Modic III; groups. HE staining was used to detect the pathological changes in endplates. The changes of Galectin-3, MMP3, Aggrecan, CCL3, and Col II were detected by immunohistochemistry, RT-PCR, and Western blot. MTT and flow cytometry were used to detect cartilage endplate cell proliferation, cell cycle, and apoptosis. RESULTS: With the progression of degeneration (from Modic I to III), the chondrocytes and density of the cartilage endplate of the intervertebral disc decreased, and the collagen arrangement of the cartilage endplate of the intervertebral disc was broken and calcified. Meanwhile, the expressions of Aggrecan, Col II, Galectin-3, Aggrecan, and CCL3 gradually decreased. After treatment with Galectin-3 inhibitor GB1107, the proliferation of rat cartilage end plate cells was significantly reduced (P < 0.05). GB1107 (25 µmol/L) also significantly promoted the apoptosis of cartilage endplate cells (P < 0.05). Moreover, the percentage of cartilage endplate cells in the G1 phase was significantly higher, while that in the G2 and S phases was significantly lower (P < 0.05). Additionally, the mRNA and protein expression levels of MMP3, CCL3, and Aggrecan in rat cartilage end plate cells were lower than those in the control group. CONCLUSIONS: Galectin-3 decreases with the progression of the cartilage endplate degeneration of the intervertebral disc. Galectin-3 may affect intervertebral disc degeneration by regulating the degradation of the extracellular matrix.

Single-cell RNA-seq analysis reveals the Wnt/Ca2+ signaling pathway with inflammation, apoptosis in nucleus pulposus degeneration.

BACKGROUND: Increasing studies have shown degeneration of nucleus pulposus cells (NPCs) as an critical part of the progression of intervertebral disc degeneration (IVDD). However, there are relatively few studies on single-cell transcriptome contrasts in human degenerated NPCs. Moreover, differences in Wnt/Ca2+ signaling in human degenerated nucleus pulposus cells have not been elucidated. The aim of this study is to investigate the differential expression of Wnt/Ca2+ signaling pathway between normal and degenerated nucleus pulposus cells in humans and try to investigate its mechanism. METHODS: We performed bioinformatics analysis using our previously published findings to construct single cell expression profiles of normal and degenerated nucleus pulposus. Then, in-depth differential analysis was used to characterize the expression of Wnt/Ca2+ signaling pathway between normal and degenerated nucleus pulposus cells in humans. RESULTS: The obtained cell data were clustered into five different chondrocytes clusters, which chondrocyte 4 and chondrocyte 5 mainly accounted for a high proportion in degenerated nucleus pulposus tissues, but rarely in normal nucleus pulposus tissues. Genes associated within the Wnt/Ca2+ signaling pathway, such as Wnt5B, FZD1, PLC (PLCB1), CaN (PPP3CA) and NAFATC1 are mainly present in chondrocyte 3, chondrocyte 4 and chondrocyte 5 from degenerated nucleus pulposus tissues. In addition, as a receptor that activates Wnt signaling pathway, LRP5 is mainly highly expressed in chondrocyte 5 of degenerated nucleus pulposus cells. Six genes, ANGPTL4, PTGES, IGFBP3, GDF15, TRIB3 and TNFRSF10B, which are associated with apoptosis and inflammatory responses, and are widespread in chondrocyte 4 and chondrocyte 5, may be closely related to degenerative of nucleus pulposus cells. CONCLUSIONS: Single-cell RNA sequencing revealed differential expression of Wnt/Ca2+ signaling in human normal and degenerated nucleus pulposus cells, and this differential expression may be closely related to the abundance of chondrocyte 4 and chondrocyte 5 in degenerated nucleus pulposus cells. In degenerated nucleus pulposus cells, LRP5 activate Wnt5B, which promotes nucleus pulposus cell apoptosis and inflammatory response by regulating the Wnt/Ca2+ signaling pathway, thereby promoting disc degeneration. ANGPTL4, IGFBP3, PTGES in chondrocyte 4 and TRIB3, GDF15, TNFRSF10B in chondrocyte 5 may play an important role in this process.

Regulation of endoplasmic reticulum stress on autophagy and apoptosis of nucleus pulposus cells in intervertebral disc degeneration and its related mechanisms.

Intervertebral disc degeneration (IVDD) is a common and frequent disease in orthopedics, which seriously affects the quality of life of patients. Endoplasmic reticulum stress (ERS)-regulated autophagy and apoptosis play an important role in nucleus pulposus (NP) cells in IVDD. Hypoxia and serum deprivation were used to induce NP cells. Cell counting kit-8 (CCK-8) assay was used to detect cell activity and immunofluorescence (IF) was applied for the appraisement of glucose regulated protein 78 (GRP78) and green fluorescent protein (GFP)-light chain 3 (LC3). Cell apoptosis was detected by flow cytometry and the expression of LC3II/I was detected by western blot. NP cells under hypoxia and serum deprivation were induced by lipopolysaccharide (LPS), and intervened by ERS inhibitor (4-phenylbutyric acid, 4-PBA) and activator (Thapsigargin, TP). Then, above functional experiments were conducted again and western blot was employed for the evaluation of autophagy-, apoptosis and ERS-related proteins. Finally, NP cells under hypoxia and serum deprivation were stimulated by LPS and intervened using apoptosis inhibitor z-Val-Ala-DL-Asp-fluoromethyl ketone (Z-VAD-FMK) and autophagy inhibitor 3-methyladenine (3-MA). CCK-8 assay, IF, flow cytometry and western blot were performed again. Besides, the levels of inflammatory cytokines were measured with enzyme-linked immunosorbent assay (ELISA) and the protein expressions of programmed death markers were estimated with western blot. It showed that serum deprivation induces autophagy and apoptosis. ERS was significantly activated by LPS in hypoxic and serum deprivation environment, and autophagy and apoptosis were significantly promoted. Overall, ERS affects the occurrence and development of IVDD by regulating autophagy, apoptosis and other programmed death.

Menstrual blood-derived mesenchymal stem cells combined with collagen I gel as a regenerative therapeutic strategy for degenerated disc after discectomy in rats.

BACKGROUND: Annulus fibrosis (AF) defects have been identified as the primary cause of disc herniation relapse and subsequent disc degeneration following discectomy. Stem cell-based tissue engineering offers a promising approach for structural repair. Menstrual blood-derived mesenchymal stem cells (MenSCs), a type of adult stem cell, have gained attention as an appealing source for clinical applications due to their potential for structure regeneration, with ease of acquisition and regardless of ethical issues. METHODS: The differential potential of MenSCs cocultured with AF cells was examined by the expression of collagen I, SCX, and CD146 using immunofluorescence. Western blot and ELISA were used to examine the expression of TGF-ß and IGF-I in coculture system. An AF defect animal model was established in tail disc of Sprague-Dawley rats (males, 8 weeks old). An injectable gel containing MenSCs (about 1*106/ml) was fabricated and transplanted into the AF defects immediately after the animal model establishment, to evaluate its repairment properties. Disc degeneration was assessed via magnetic resonance (MR) imaging and histological staining. Immunohistochemical analysis was performed to assess the expression of aggrecan, MMP13, TGF-ß and IGF-I in discs with different treatments. Apoptosis in the discs was evaluated using TUNEL, caspase3, and caspase 8 immunofluorescence staining. RESULTS: Coculturing MenSCs with AF cells demonstrated ability to express collagen I and biomarkers of AF cells. Moreover, the coculture system presented upregulation of the growth factors TGF-ß and IGF-I. After 12 weeks, discs treated with MenSCs gel exhibited significantly lower Pffirrmann scores (2.29 ± 0.18), compared to discs treated with MenSCs (3.43 ± 0.37, p < 0.05) or gel (3.71 ± 0.29, p < 0.01) alone. There is significant higher MR index in disc treated with MenSCs gel than that treated with MenSCs (0.51 ± 0.05 vs. 0.24 ± 0.04, p < 0.01) or gel (0.51 ± 0.05 vs. 0.26 ± 0.06, p < 0.01) alone. Additionally, MenSCs gel demonstrated preservation of the structure of degenerated discs, as indicated by histological scoring (5.43 ± 0.43 vs. 9.71 ± 1.04 in MenSCs group and 10.86 ± 0.63 in gel group, both p < 0.01), increased aggrecan expression, and decreased MMP13 expression in vivo. Furthermore, the percentage of TUNEL and caspase 3-positive cells in the disc treated with MenSCs Gel was significantly lower than those treated with gel alone and MenSCs alone. The expression of TGF-ß and IGF-I was higher in discs treated with MenSCs gel or MenSCs alone than in those treated with gel alone. CONCLUSION: MenSCs embedded in collagen I gel has the potential to preserve the disc structure and prevent disc degeneration after discectomy, which was probably attributed to the paracrine of growth factors of MenSCs.

[Genetic factors in degenerative disc disease]. / Rol' geneticheskikh faktorov v razvitii degenerativno-distroficheskogo porazheniya mezhpozvonkovykh diskov.

OBJECTIVE: To analyze available literature data on the role of genetic factors in degenerative disc disease. METHODOLOGY: We reviewed the PubMed, MEDLINE, Cohrane Library, e-Library databases using the following keywords: degenerative spine lesions, intervertebral disc herniation, pathogenesis, genetic regulation. RESULTS: Searching depth was 2002-2022. We reviewed 84 references. Exclusion criteria: duplicate publications, reviews without detailed description of results, opinions. Finally, we included 43 the most significant studies. CONCLUSION: There are literature data on proinflammatory cytokines, growth factors and osteodestructive processes in pathogenesis of degenerative disc disease. However, there is only fragmentary information about the role of genetic regulation of these processes. Some factors, such as microRNA, TGF-b, VEGF, MMP are still poorly understood.

Ginsenoside Rg1 relieves rat intervertebral disc degeneration and inhibits IL-1ß-induced nucleus pulposus cell apoptosis and inflammation via NF-κB signaling pathway.

The study aimed to investigate the effect of ginsenoside Rg1 on intervertebral disc degeneration (IVDD) in rats and IL-1ß-induced nucleus pulposus (NP) cells, and explore its underlying mechanism. Forty IVDD rat models were divided into the IVDD group, low-dose (L-Rg1) group (intraperitoneal injection of 20 mg/kg/d ginsenoside Rg1), medium-dose (M-Rg1) group (intraperitoneal injection of 40 mg/kg/d ginsenoside Rg1), and high-dose (H-Rg1) group (intraperitoneal injection of 80 mg/kg/d ginsenoside Rg1). The pathological change was observed by HE and safranin O-fast green staining. The expression of IL-1ß, IL-6, TNF-α, MMP3, aggrecan, and collagen II was detected. The expression of NF-κB p65 in IVD tissues was detected. Rat NP cells were induced by IL-1ß to simulate IVDD environment and divided into the control group, IL-1ß group, and 20, 50, and 100 µmol/L Rg1 groups. The cell proliferation activity, the apoptosis, and the expression of IL-6, TNF-α, MMP3, aggrecan, collagen II, and NF-κB pathway-related protein were detected. In IVDD rats, ginsenoside Rg1 improved the pathology of IVD tissues; suppressed the expression of IL-1ß, IL-6, TNF-α, aggrecan, and collagen II; and inhibited the expression of p-p65/p65 and nuclear translocation of p65, to alleviate the IVDD progression. In the IL-1ß-induced NP cells, ginsenoside Rg1 also improved the cell proliferation and inhibited the apoptosis and the expression of IL-6, TNF-α, aggrecan, collagen II, p-p65/p65, and IκK in a dose-dependent manner. Ginsenoside Rg1 alleviated IVDD in rats and inhibited apoptosis, inflammatory response, and ECM degradation in IL-1ß-induced NP cells. And Rg1 may exert its effect via inhibiting the activation of NF-κB signaling pathway.

Platelet-rich plasma-derived extracellular vesicles inhibit NF-κB/NLRP3 pathway-mediated pyroptosis in intervertebral disc degeneration via the MALAT1/microRNA-217/SIRT1 axis.

BACKGROUND: Intervertebral disc degeneration (IDD) is a main contributor to lower back pain, and compression stress-induced apoptosis of nucleus pulposus (NP) cells and extracellular matrix (ECM) degradation has been implicated in the IDD progression. The functions of platelet-rich plasma (PRP)-derived extracellular vesicles (PRP-EVs) in regulating these biological processes remain unclear in IDD. Here, we aimed to investigate the key role of long noncoding RNA (lncRNA) MALAT1 incorporated in PRP-EVs in IDD. METHODS: Tert-butyl hydroperoxide (TBHP)-induced damage in NP cells was treated with PRP-EVs extracted from healthy volunteers, followed by MTT, EdU, TUNEL, and Western blot assays. IDD mice were also treated with PRP-EVs. Histomorphological and pathological changes were evaluated. The pyroptosis of cells and the degradation of ECM were detected by ELISA and immunohistochemistry. We screened the differentially expressed lncRNAs in NP cells after PRP-EVs treatment by microarray analysis. The downstream targets of MALAT1 in NP cells were predicted and validated by rescue experiments. FINDINGS: TBHP induction reduced cell proliferation and exacerbated pyroptosis and ECM degradation, and PRP-EVs inhibited TBHP-induced cell damage. PRP-EVs-treated mice with IDD had reduced Thompson scores, increased NP tissue content, and restored ECM. PRP-EVs upregulated MALAT1 expression in vivo and in vitro, whereas MALAT1 downregulation exacerbated NP cell pyroptosis and ECM degradation. MALAT1 upregulated SIRT1 expression by downregulating microRNA (miR)-217 in NP cells. SIRT1 blocked the NF-κB/NLRP3 pathway-mediated pyroptosis, thereby alleviating IDD. INTERPRETATION: PRP-EVs deliver MALAT1 to regulate miR-217/SIRT1, thereby controlling NP cell pyroptosis in IDD.

Modic Changes in the Lumbar Spine: Exploring Their Association with Abdominal Aortic Calcification as a Potential Indicator of Systemic Atherosclerosis.

BACKGROUND: This was a cross-sectional study on the correlation between abdominal aortic calcification (AAC) and Modic changes (MC). Little is known regarding the etiology of MC in the lumbar spine. Currently, insufficient vascularization of the endplate has been proposed to contribute to the appearance of MC. Our objective was to investigate whether AAC, a marker for a poor vascular status, is associated with MC in patients suffering from degenerative disc disease. METHODS: Radiologic images of patients (n = 130) suffering from degenerative lumbar disc disease were reviewed. Type and severity of MC were assessed using magnetic resonance images, and severity of AAC was evaluated using computed tomography images or fluoroscopy. Both items were dichotomized into minimal and relevant grades. The correlation between them was studied using Spearman's correlation test, with age as a covariate. RESULTS: Of the patients, 113 (87%) demonstrated MC (31% type I, 63% type II, and 6% type III) (55% relevant grade), and 68% had AAC (44% relevant grade). Spearman statistical analysis revealed that AAC was correlated with age (P < 0.001), whereas MC were not (P = 0.142). AAC severity was significantly correlated with MC, remaining so after age adjustment (P < 0.05). While MC type I lacked correlation with AAC, MC type II were significantly correlated with AAC (0.288, P = 0.015); however, this association lost significance after adjusting for age (P = 0.057). CONCLUSIONS: AAC and MC (mainly MC type II) are associated, indicating that reduced blood supply or even a poor systemic vascularization status due to atherosclerotic disease may play a role in the formation of MC. Future studies focusing on the etiology of MC should pay more attention to patients' vascular status and determinants of abdominal aorta calcification.

Injectable pathological microenvironment-responsive anti-inflammatory hydrogels for ameliorating intervertebral disc degeneration.

Chronic local inflammation and resulting cellular dysfunction of nucleus pulposus (NP) cells are important pathogenic factors of intervertebral disc degeneration (IDD). Injectable pathological microenvironment-responsive hydrogels hold significant potential for treating IDD by adapting to dynamic microenvironment of IDD. Herein, we proposed an injectable gelatin-based hydrogel drug delivery system that could respond to the pathological microenvironment of IDD for controlled release of anti-inflammatory drug to promote degenerative NP repair. The hydrogel system was prepared by conjugating phenylboronic acid-modified gelatin methacryloyl (GP) with the naturally extracted anti-inflammatory drug epigallocatechin-3-gallate (EGCG) through dynamic boronic esters. The hydrogel exhibited excellent degradability, injectability, antioxidant properties, anti-inflammatory effects, and biocompatibility. It also displayed responsive-release of EGCG under high reactive oxygen species (ROS) levels and acidic conditions. The hydrogel demonstrated remarkable cytoprotective effects on NP cells in both hyperactive ROS environments and inflammatory cytokine-overexpressed environments in vitro. In vivo studies revealed that the hydrogel injected in situ could effectively ameliorate the intervertebral disc degeneration by maintaining the disc height and NP tissue structure in a rat IDD model. The hydrogel system exhibited excellent biocompatibility and responsive-release of diol-containing drugs in pathological microenvironments, indicating its potential application as a drug delivery platform.

IVD fibrosis and disc collapse comprehensively aggravate vertebral body disuse osteoporosis and zygapophyseal joint osteoarthritis by posteriorly shifting the load transmission pattern.

BACKGROUND: Disuse is a typical phenotype of osteoporosis, but the underlying mechanism has yet to be identified in elderly patients. Disc collapse and intervertebral disc (IVD) fibrosis are two main pathological changes in IVD degeneration (IDD) progression, given that these changes affect load transmission patterns, which may lead to disuse osteoporosis of vertebral bodies and zygapophyseal joint (ZJ) osteoarthritis (ZJOA) biomechanically. METHODS: Clinical data from 59 patients were collected retrospectively. Patient vertebral bony density, ZJOA grade, and disc collapse status were judged via CT. The IVD fibrosis grade was determined based on the FA measurements. Regression analyses identified potential independent risk factors for osteoporosis and ZJOA. L4-L5 numerical models with and without disc collapse and IVD fibrosis were constructed; stress distributions on the bony endplate (BEP) and zygapophyseal joint (ZJ) cartilages were computed in models with and without disc collapse and IVD fibrosis. RESULTS: A significantly lower disc height ratio and significantly greater FA were recorded in patients with ZJOA. A significant correlation was observed between lower HU values and two parameters related to IDD progression. These factors were also proven to be independent risk factors for both osteoporosis and ZJOA. Correspondingly, compared to the intact model without IDD. Lower stress on vertebral bodies and greater stress on ZJOA can be simultaneously recorded in models of disc collapse and IVD fibrosis. CONCLUSIONS: IVD fibrosis and disc collapse simultaneously aggravate vertebral body disuse osteoporosis and ZJOA by posteriorly shifting the load transmission pattern.

Association between lumbar intervertebral vacuum phenomenon severity and posterior paraspinal muscle atrophy in patients undergoing spine surgery.

PURPOSE: Intervertebral vacuum phenomenon (IVP) and paraspinal muscular atrophy are age-related changes in the lumbar spine. The relationship between both parameters has not been investigated. We aimed to analyze the correlation between IVP and paraspinal muscular atrophy in addition to describing the lumbar vacuum severity (LVS) scale, a new parameter to estimate lumbar degeneration. METHODS: We analyzed patients undergoing spine surgery between 2014 and 2016. IVP severity was assessed utilizing CT scans. The combination of vacuum severity on each lumbar level was used to define the LVS scale, which was classified into mild, moderate and severe. MRIs were used to evaluate paraspinal muscular fatty infiltration of the multifidus and erector spinae. The association of fatty infiltration with the severity of IVP at each lumbar level was assessed with a univariable and multivariable ordinal regression model. RESULTS: Two hundred and sixty-seven patients were included in our study (128 females and 139 males) with a mean age of 62.6 years (55.1-71.2). Multivariate analysis adjusted for age, BMI and sex showed positive correlations between LVS-scale severity and fatty infiltration in the multifidus and erector spinae, whereas no correlation was observed in the psoas muscle. CONCLUSION: IVP severity is positively correlated with paraspinal muscular fatty infiltration. This correlation was stronger for the multifidus than the erector spinae. No correlations were observed in the psoas muscle. The lumbar vacuum severity scale was significantly correlated with advanced disc degeneration with vacuum phenomenon.

A novel missense COL9A3 variant in a pedigree with multiple lumbar disc herniation.

Trp3 allele in COL9A3 gene has been widely studied in populations with intervertebral disc disease. We identified a novel pathogenic variant in COL9A3 gene in a pedigree with multiple lumbar disc herniation (LDH). The proband was a 14-year-old boy who developed LDH at the L4/5 and L5/S1 spinal segments. His father, paternal aunt and grandfather were diagnosed with LDH at an age of 35, 30 and 23, respectively. By applying whole exome sequencing, a heterozygous missense variant (c.1150C > T, p.Arg384Trp) in COL9A3 was identified. According to the ACMG guidelines, this variant is predicted to be pathogenic. In addition, prediction tools found COL9A3 protein of this variant a reduced stability, some changed charge properties, and an altered spatial conformation. Findings expanded the mutational spectrum of LDH and contributed to the understanding of COL9A3 in the pathogenesis of LDH.

The relationship between structural changes in paraspinal muscles and intervertebral disc and facet joint degeneration in the lumbar spine of rats.

BACKGROUND: Degenerative spine disease is one of the largest causes of disability worldwide and has a multifactorial aetiology. Determining the leading causes of this multifactorial disease could help create new treatment approaches. PURPOSE: Study the impact of degenerative changes in the paraspinal muscles caused by local (prolonged compression) or systemic (high-fat diet) factors on the structure of the intervertebral discs (IVDs) and facet joints of the lumbar spine in rats. METHODS: The study was conducted using two animal models to create degenerative changes in the paraspinal muscles of 10 white laboratory rats for 90 days and five control rats: 1) high-fat diet model (model 1) involved keeping the rats on a high calorie diet; 2) compression model (model 2) involved binding the paraspinal muscles from L2 to S1 using non-absorbable sutures. Histological analysis for the facet joints and IVDs of rats (at the L1-L4 level) with semi-quantitative analysis of the structure conducted used by degeneration grading system for IVDs and cartilage degeneration score (OARSI) for facet joint. RESULTS: In both models, 90 days after the experiment, the degenerative changes observed in the rats' IVDs were more severe in the annulus fibrosus than in the nucleus pulposus. The height of the IVD in model 1 did not differ from the control group, but in the model 2 was 1.3 times greater (p < 0.001) compared with control. Degenerative changes in the IVD were scored out 5.3 ± 1.7 in model 1 and 5.32 ± 2.1 in model 2 of a possible 16. The height of the articular cartilage of the facet joints was smaller by 1.5 times (p < 0.001) and 1.4 times (p < 0.001) in model 1 and model 2, respectively, compared to the control. Degenerative changes of facet joint were scored out 3.7 ± 0.6 in model 1 and 3.8 ± 0.6 in model 2 of five points according to the cartilage degeneration score. CONCLUSIONS: It was determined that rats who had structural changes in the lumbar paraspinal muscles as a result of being kept on a high-fat diet or subjected to prolonged compression for 90 days, showed degenerative changes in intervertebral discs and osteoarthritis in facet joints of lumbar spine.

Imaging of Discogenic and Vertebrogenic Pain.

Chronic low back pain is a major source of pain and disability globally involving multifactorial causes. Historically, intervertebral disc degeneration and disruption have been associated as primary back pain triggers of the anterior column, termed "discogenic pain." Recently, the vertebral endplates have been identified as another possible pain trigger of the anterior column. This "endplate-driven" model, defined "vertebrogenic pain," is often interconnected with disc degeneration. Diagnosis of vertebrogenic and discogenic pain relies on imaging techniques that isolate pain generators and exclude comorbid conditions. Traditional methods, like radiographs and discography, are augmented by more sensitive methods, including SPECT, CT, and MRI. Morphologic MRI is pivotal in revealing indicators of vertebrogenic (eg, Modic endplate changes) and discogenic pain (eg, disc degeneration and annular fissures). More advanced methods, like ultra-short-echo time imaging, and quantitative MRI further amplify MRI's accuracy in the detection of painful endplate and disc pathology. This review explores the pathophysiology of vertebrogenic and discogenic pain as well as the impact of different imaging modalities in the diagnosis of low back pain. We hope this information can help identify patients who may benefit from personalized clinical treatment and image-guided therapies.

Relationship between lumbar spinal stenosis and axial muscle wasting.

BACKGROUND CONTEXT: Although the effect of lumbar spinal stenosis (LSS) on the lower extremities is well documented, limited research exists on the effect of spinal stenosis on the posterior paraspinal musculature (PPM). Similar to neurogenic claudication, moderate to severe spinal canal compression can also interfere with the innervation of the PPM, which may result in atrophy and increased fatty infiltration (FI). PURPOSE: This study aims to assess the association between LSS and atrophy of the PPM. STUDY DESIGN: Retrospective cross-sectional study. PATIENT SAMPLE: Patients undergoing MRI scans at a tertiary orthopedic center for low back pain or as part of a preoperative evaluation. OUTCOME MEASURES: The functional cross-sectional area (fCSA) and percent fatty infiltration (FI) of the PPM at L4. METHODS: Lumbar MRIs of patients at a tertiary orthopedic center indicated due to lower back pain (LBP) or as a presurgical workup were analyzed. Patients with previous spinal fusion surgery or scoliosis were excluded. LSS was assessed according to the Schizas classification at all lumbar levels. The cross-sectional area of the PPM was measured on a T2-weighted MRI sequence at the upper endplate of L4. The fCSA and fatty infiltration (FI) were calculated using custom software. Crude differences in FI and fCSA between patients with no stenosis and at least mild stenosis were tested with the Wilcoxon signed-rank test. To account for possible confounders, a multivariable linear regression model was used to adjust for age, sex, body mass index (BMI), and disc degeneration. A subgroup analysis according to MRI indication was performed. RESULTS: A total of 522 (55.7% female) patients were included. The median age was 61 years (IQR: 51-71). The greatest degree of moderate and severe stenosis was found at L4/5, 15.7%, and 9.2%, respectively. Stenosis was the least severe at L5/S1 and was found to be 2% for moderate and 0.2% for severe stenosis. The Wilcoxon test showed significantly increased FI of the PPM with stenosis at any lumbar level (p<.001), although no significant decrease in fCSA was observed. The multivariable regression model showed a significant increase in FI with increased LSS at L1/2, L2/3, and L3/4 (p=.013, p<.01 and p=.003). The severity of LSS at L4/5 showed a positive association with the fCSA (p=.019). The subgroup analysis showed, the effect of LSS was more pronounced in nonsurgical patients than in patients undergoing surgery. CONCLUSIONS: In this study, we demonstrated a significant and independent association between LSS and the composition of the PPM, which was dependent on the level of LSS relative to the PPM. In addition to neurogenic claudication, patients with LSS might be especially susceptible to axial muscle wasting, which could worsen LSS due to increased spinal instability, leading to a positive feedback loop.

Prevalence and distribution of Schmorl node and endplate signal change, and correlation with disc degeneration in a population-based cohort: the Wakayama Spine Study.

PURPOSE: Degenerative spinal conditions, including disc degeneration (DD), Schmorl nodes (SN), and endplate signal changes (ESC), are pervasive age-associated phenomena that critically affect spinal health. Despite their prevalence, a comprehensive exploration of their distribution and correlations is lacking. This study examined the prevalence, distribution, and correlation of DD, SN, and ESC across the entire spine in a population-based cohort. METHODS: The Wakayama Spine Study included 975 participants (324 men, mean age 67.2 years; 651 women, mean age 66.0 years). Magnetic resonance imaging (MRI) was used to evaluate the intervertebral space from C2/3 to L5/S1. DD was classified using Pfirrmann's system, ESC was identified by diffuse high-intensity signal changes on the endplates, and SN was defined as a herniation pit with a hypointense signal. We assessed the prevalence and distribution of SN, ESC, and DD across the entire spine. The correlations among these factors were examined. RESULTS: Prevalence of ≥ 1 SN over the entire spine was 71% in men and 77% in women, while prevalence of ≥ 1 ESC was 57.9% in men and 56.3% in women. The prevalence of ESC and SN in the thoracic region was the highest among the three regions in both sexes. Positive linear correlations were observed between the number of SN and DD (r = 0.41, p < 0.001) and the number of ESC and DD (r = 0.40, p < 0.001), but weak correlations were found between the number of SN and ESC (r = 0.29, p < 0.001). CONCLUSION: The prevalence and distribution of SN and ESC over the entire spine were observed, and correlations between SN, ESC, and DD were established. This population-based cohort study provides a comprehensive analysis of these factors.

DNMT3a-mediated methylation of PPARγ promote intervertebral disc degeneration by regulating the NF-κB pathway.

Intervertebral disc degeneration (IVDD) is a common chronic musculoskeletal disease that causes chronic low back pain and imposes an immense financial strain on patients. The pathological mechanisms underlying IVDD have not been fully elucidated. The development of IVDD is closely associated with abnormal epigenetic changes, suggesting that IVDD progression may be controlled by epigenetic mechanisms. Consequently, this study aimed to investigate the role of epigenetic regulation, including DNA methyltransferase 3a (DNMT3a)-mediated methylation and peroxisome proliferator-activated receptor γ (PPARγ) inhibition, in IVDD development. The expression of DNMT3a and PPARγ in early and late IVDD of nucleus pulposus (NP) tissues was detected using immunohistochemistry and western blotting analyses. Cellularly, DNMT3a inhibition significantly inhibited IL-1ß-induced apoptosis and extracellular matrix (ECM) degradation in rat NP cells. Pretreatment with T0070907, a specific inhibitor of PPARγ, significantly reversed the anti-apoptotic and ECM degradation effects of DNMT3a inhibition. Mechanistically, DNMT3a modified PPARγ promoter hypermethylation to activate the nuclear factor-κB (NF-κB) pathway. DNMT3a inhibition alleviated IVDD progression. Conclusively, the results of this study show that DNMT3a activates the NF-κB pathway by modifying PPARγ promoter hypermethylation to promote apoptosis and ECM degradation. Therefore, we believe that the ability of DNMT3a to mediate the PPARγ/NF-κB axis may provide new ideas for the potential pathogenesis of IVDD and may become an attractive target for the treatment of IVDD.

The Impact of Cervical Degeneration and Sagittal Balance on Retro-Odontoid Soft-Tissue Thickness.

OBJECTIVE: To investigate whether retro-odontoid soft-tissue thickness (ROSTT) is associated with cervical degeneration, cervical spine mobility, and sagittal balance of cervical spine. METHODS: The data of 151 patients who presented at our hospital with cervical spondylosis were reviewed. The ROSTT was measured using T1-weighted sagittal cervical magnetic resonance imaging findings. The assessment of the degree of cervical intervertebral disc degeneration (IVDD) was conducted using sagittal T2-weighted imaging. The T1 slope (T1S), C0-C2 angle, C1-C2 angle, C2-C7 angle, C1-C7 sagittal vertical axis and C2-C7 sagittal vertical axis were measured. The range of motion was assessed by measuring the flexion-extension radiographs. According to the ROSTT, those measuring less than 3 mm were classified as normal group and those measuring larger than 3 mm were classified as thickened group. RESULTS: The thickened group had larger cervical IVDD grade, age, C2-C7 angle, and T1S compared to the normal group (all P < 0.05). Additionally, the C0-C2 angle was significantly smaller in the thickened group than in the normal group (P < 0.05). ROSTT showed a negative correlation with C0-C2 angle (r = -0.181, P < 0.05), but positive correlations with both C2-C7 angle (r = 0.255, P < 0.05) and T1S (r = 0.240, P < 0.05). Furthermore, ROSTT was positively correlated with age (r = 0277, P < 0.05) and cervical IVDD grade (Spearman, r = 0.299, P < 0.05). CONCLUSIONS: Cervical sagittal balance and cervical degeneration have a significant impact on ROSTT. Patients with a higher T1S and severe cervical degeneration are more likely to result in greater ROSTT.

Potential Use of Extracellular Vesicles in the Treatment of Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IVDD) is a major cause of low back pain, and several studies have evaluated the efficacy of extracellular vesicles (EVs) in the treatment of IVDD. The databases PubMed, Embase, and Cochrane Library were systematically searched from inception to the end of 2022 to identify studies investigating the therapeutic potential of cell-derived EVs for IVDD treatment. The following outcome measures were utilized: magnetic resonance imaging (MRI) Pfirrmann grading system, disc height index (DHI), histological grading, and apoptosis rate. A comprehensive meta-analysis was conducted, including a total of 13 articles comprising 19 studies involving 218 experimental animals. Comparative analysis between normal cell-derived EVs and placebo revealed significant reductions in MRI grade, increased DHI values, decreased nucleus pulposus cell apoptosis rates, and improved tissue grades. These findings collectively demonstrate the effective inhibition of IVDD through the application of EVs derived from cells. In conclusion, this study provides an updated synthesis of evidence supporting the efficacy of EVs as a promising therapeutic approach for IVDD treatment.