Intervertebral disc degeneration (IVDD) is a leading cause of low back pain (LBP), contributing significantly to global disability and productivity loss. Its pathogenesis involves complex processes, including inflammation, cellular senescence, angiogenesis, fibrosis, neural ingrowth, and sensitization. Emerging evidence highlights macrophages as central immune regulators infiltrating degenerated discs, with macrophage polarization implicated in IVDD progression. However, the mechanisms linking macrophage polarization to IVDD pathology remain poorly elucidated.
A comprehensive literature review was conducted by searching major databases (PubMed, Web of Science, and Scopus) for studies published in the last decade (2014–2024). Keywords included “intervertebral disc degeneration,” “macrophage polarization,” “inflammation,” “senescence,” and “therapeutic strategies.” Relevant articles were selected, analyzed, and synthesized to evaluate the role of macrophage polarization in IVDD.
Macrophage polarization dynamically influences IVDD through multiple pathways. Pro-inflammatory M1 macrophages exacerbate disc degeneration by amplifying inflammatory cytokines (e.g., TNF-α, IL-1β), promoting cellular senescence, and stimulating abnormal angiogenesis and neural ingrowth. In contrast, anti-inflammatory M2 macrophages may mitigate degeneration by suppressing inflammation and enhancing tissue repair. Therapeutic strategies targeting macrophage polarization include pharmacological agents (e.g., cytokines, small-molecule inhibitors), biologic therapies, gene editing, and physical interventions. Challenges persist, such as incomplete understanding of polarization triggers, lack of targeted delivery systems, and limited translational success in preclinical models.
Macrophage polarization is a pivotal regulator of IVDD pathology, offering promising therapeutic targets. Future research should focus on elucidating polarization mechanisms, optimizing spatiotemporal control of macrophage phenotypes, and developing personalized therapies. Addressing these challenges may advance innovative strategies to halt or reverse IVDD progression, ultimately improving clinical outcomes for LBP patients.
Disc degeneration (DD) is accompanied by biomechanical changes in the intervertebral discs. The lamellae of the annulus fibrosus (AF) are interconnected through the interlamellar matrix (ILM). The ILM contains interlamellar cross-bridges, connecting the lamellae radially in three dimensions. Weakening of the ILM and the cross-bridges could contribute to delamination between the lamellae, reducing their ability to resist loads and thus contributing to loss of AF integrity associated with the development and progression of degeneration. The objective of the present study was to quantify the differences in interlamellar mechanical properties of fresh AF samples from surgical DD individuals compared to AF samples from non-DD donors.
An interlamellar peel test was performed on fresh AF tissue collected from DD surgeries (n = 36) and non-DD organ donors (n = 13). The tissue was peeled at 0.5 mm/s until complete separation. Interlamellar mechanical properties were calculated from the force-displacement curve.
Samples from DD individuals had lower Peel Stiffness (p = 0.001), Peel Strength (p = 0.001), Peel Toughness (p = 0.0009), and Standard Deviation of the Peel Stress (p = 0.02) compared to the tissue from non-DD organ donors. Age had moderate negative correlations with Peel Stiffness (R = −0.59), Peel Strength (R = −0.66), and Peel Toughness (R = −0.69) for non-DD samples only.
The mechanical integrity of the ILM was determined to be lower in surgical DD individuals compared to non-DD donors. Aging alone may not have affected the results, and rather, loss of the integrity of ILM during disease progression appeared to have significantly contributed to the differences observed. This study provides new mechanical insights into the delamination often observed in the AF of surgical DD individuals. Future biochemical and immunolocalization studies, integrated with mechanical data, will aim to understand the role of collagen and elastin structure and composition in the decreased mechanical integrity of affected tissues.
This study tested the hypothesis that asymmetric dynamic loading alone or in combination with static loading influences the morphological and biological characteristics of the intervertebral disc (IVD) cells in an ex vivo model.
Bovine caudal IVDs were assigned to four groups: (1) Parallel dynamic load (1 h) + free swelling (23 h); (2) Parallel dynamic load (1 h) + static load (23 h); (3) Wedge dynamic load (1 h) + free swelling (23 h); (4) Wedge dynamic load (1 h) + static load (23 h). IVD structure was assessed with measurements of height loss and histological staining. IVD tissue and cellular responses were also measured.
Diurnal dynamic loading and free swelling recovery could maintain cell viability and the gene expression of organ-cultured discs at their physiological level. Diurnal dynamic loading followed by static loading resulted in a degenerative condition, as indicated by lower cell viability, lower anabolic, and higher catabolic gene expression. Under the dynamic load + free swelling load regime, wedge loading upregulated the ACAN gene expression level in the concave and convex sides of the annulus fibrosus (AF) compared with day 0 healthy control. Under the dynamic load + static loading regime, the MMP1 gene expression showed a trend of increase in the concave and convex sides of the wedge group; the MMP13 gene expression showed a trend of increase in the concave side of the wedge group. The nucleus pulposus (NP) tissue in the wedge group showed a trend of protrusion toward the convex side.
Dynamic loading followed by continuous static loading negatively modulates the phenotype of IVD cells in this organ culture model. Comparable to the free swelling treatment after dynamic loading, physical treatment to reduce the stress on the IVD, even temporarily, may help to prevent the acceleration of deformity and degeneration. These results indicate that asymmetric loading followed by static loading may be used to mimic pathological changes of the IVD in spinal deformity.
Low back pain is a significant burden worldwide, and intervertebral disc degeneration (IVDD) is identified as the primary cause. Recent research has emphasized the significant role of circadian rhythms (CRs) and immunity in affecting intervertebral discs (IVD). However, the influence of circadian rhythms and immunity on the mechanism of IVDD remains unclear. This study aimed to identify and validate key rhythm-related genes in IVDD and analyze their correlation with immune cell infiltration.
Two gene expression profiles related to IVDD and rhythm-related genes were obtained from the Gene Expression Omnibus and GeneCards databases to identify differentially expressed rhythm-related genes (DERGs). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene set enrichment analysis (GSEA) were conducted to explore the biological functions of these genes. LASSO regression and SVM algorithms were employed to identify hub genes. We subsequently investigated the correlation between hub rhythm-related genes and immune cell infiltration. Finally, nucleus pulposus-derived mesenchymal stem cells (NPMSCs) were isolated from normal and degenerative human IVD tissues. Hub rhythm-related genes expression in NPMSCs was confirmed by real-time quantitative PCR (RT-qPCR).
Six hub genes related to CRs (CCND1, FOXO1, FRMD8, NTRK2, PRRT1, and TFPI) were screened out. Immune infiltration analysis revealed that the IVDD group had significantly more M0 macrophages and significantly fewer follicular helper T cells than those of the control group. Specifically, M0 macrophages were significantly associated with FRMD8, PRRT1, and TFPI. T follicular helper cells were significantly associated with FRDM8, FOXO1, and CCND1. We further confirmed that CCND1, FRMD8, NTRK2, and TFPI were dysrhythmic within NPMSCs from degenerated IVD in vitro.
Six genes (CCND1, FOXO1, FRMD8, NTRK2, PRRT1 and TFPI) linked to circadian rhythms associated with IVDD progression, together with immunity. The identification of these DEGs may provide new insights for the diagnosis and treatment of IVDD.
Subject-specific musculoskeletal models may be used to estimate spine loads that cannot be measured in vivo. Model generation methods may use detailed measurements extracted from medical imaging, but it may be possible to create accurate models without these measurements. We aimed to determine which physiological and anthropometric factors are associated with spine loading and should be accounted for in model creation.
We created models of 440 subjects from the Framingham Heart Study Multi-detector CT Study, extracting muscle morphology and spine profile information from CT scans of the trunk. Five lifting activities were simulated, and compressive and shear loading estimates were produced. We performed principal component analysis on the loading data from three locations in the spine, as well as univariate correlations between predictor variables and each principal component (PC). We identified multivariate predictive regression models for each PC and individual loading estimate.
A single PC explained 90% of the variability in compressive loading, while four PCs were identified that explained 10%–37% individually, 86% in total, of the variability in shear loading. Univariate analysis showed that body weight, BMI, lean mass, and waist circumference were most associated with the compression PC and first shear PC. Multivariate regression modeling showed predictor variables predicted 94% of the variability in the compression PC, but only 54% in the first shear PC, with body weight having the highest contribution. Additional shear PCs were less predictable. Level- and activity-specific compressive loading was predicted using a limited set of physiological and anthropometric factors.
This work identifies easily measured characteristics, particularly weight and height, along with sex, associated with subject-specific loading estimates. It suggests that compressive loading, or models to evaluate compressive loading, may be based on a limited set of anthropometric attributes. Shear loading appears more complex and may require additional information not captured in the set of factors we examined.
Intervertebral disk (IVD) degeneration is associated with lower back pain and aging; however, the mechanisms underlying age-related changes and the changes in macrophage polarization in aging intervertebral disks require further elucidation. The aim of this study was to evaluate changes in macrophages, the differential expression of senescence genes, and their relationship with hub genes in IVDs during aging in mice.
Twenty-eight male wild C57 mice aged 4 weeks were divided into two groups. Four mice per group were selected for high-throughput sequencing and 10 for tail IVD immunohistochemical analysis. Adult and aged mouse IVD specimens were stained with hematoxylin–eosin, Fast Green, and Alcian Blue to determine collagen (Col) 1, Col2, proteoglycan, P16, P21, P53, CD11b, CD86, CD206, IL-1, TGF-β, and IL-4 expression. High-throughput sequencing was performed on adult and aged mouse IVD tissues.
Aged mouse IVDs showed reduced height and marked degeneration, with decreased Col2 and proteoglycan expression and increased Col1 expression. The expression of senescence markers, senescence-associated IL-1, TGF-β, and IL-4, and macrophage-related markers, CD11b, CD86, and CD206, increased markedly with age. High-throughput sequencing revealed 1975 differentially expressed genes in adult and aged mice, with 797 genes showing upregulated expression (top five: Kcna7, Mmp9, Panx3, Myl10, and Bglap) and 1178 showing downregulated expression (top five: Srd5a2, Slc38a5, Gm47283, Npy, and Pcdh8). Gene Ontology and pathway enrichment analyses highlighted aging-related cellular components, biological processes, and metabolic pathways. The identified hub genes included Cox5a, Ndufs6, and Ndufb9.
Disk senescence and reduced height in aged mice are linked to upregulated expression of senescence-associated phenotypes and macrophage polarization markers. These findings suggest that macrophages and differential gene expression play key roles in age-related IVD degeneration, indicating that they can be used as potential targets for therapeutic intervention.
This study aims to examine the role of translation factors (TF) in intervertebral disc degeneration (IVDD) and to evaluate their clinical relevance through unsupervised clustering methods.
Gene expression data were retrieved from the GEO database, and the expression levels of translation factor-related genes (TFGs) were extracted for analysis.
Two distinct molecular clusters were identified based on the differential expression of nine significantly altered TFGs. Immune infiltration was notably higher in Cluster C2 compared to Cluster C1. Subsequently, two gene clusters were identified based on the differentially expressed genes between the clusters. A Sankey diagram illustrated a high degree of consistency between the molecular clusters and the gene clusters. Additionally, four machine learning models were developed and evaluated, with the SVM model being utilized to construct a nomogram for predicting the incidence of IVDD. Validation using external datasets and clinical samples confirmed the low expression of EEF2K, which was further analyzed in a pan-cancer context.
The identification and comprehensive assessment of the two molecular clusters offer significant insights for the classification and treatment of individuals with IVDD.
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