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Intervertebral disc degeneration (IVDD) represents a primary cause of chronic low back pain and disability worldwide and is characterized by the progressive loss of structural integrity within the nucleus pulposus (NP), annulus fibrosus, and cartilaginous endplates. This pathological process involves a complex interplay of mechanical stress, metabolic disturbances, and cellular dysfunction, ultimately leading to a significant reduction in disc elasticity and stability.
While inflammation and immune cell infiltration have been implicated in IVDD progression, the specific immune populations responsible for matrix destruction and disc deterioration remain poorly defined. In a recent Genes & Diseases study, researchers from the First Affiliated Hospital of Anhui Medical University employed an integrated multi-omic approach to identify key immune drivers of IVDD and reveal novel therapeutic targets.
The authors constructed a comprehensive multi-omic atlas of degenerating intervertebral discs by integrating single-cell RNA sequencing, cell–cell communication analysis, exosome biology, machine learning-based feature prioritization, and Mendelian randomization. Through this framework, they identified a distinct population of SPP1-expressing (osteopontin-positive) macrophages that was significantly expanded in degenerating discs and spatially localized near NP cells, suggesting a pivotal role in shaping the degenerative microenvironment.
Single-cell RNA sequencing identifies SPP1+ macrophages in degenerating intervertebral discs
(A, B) UMAP visualization of cell populations in the Operation and Sham operation groups, with SPP1+ Mac and SPP1- Mac populations highlighted. (C) Cell frequency analysis showing increased SPP1+ macrophages in the Operation group. (D) Heatmap of differentially expressed genes across cell populations. (E) UMAP feature plots showing the expression of marker genes, including Spp1, Emb1, Fn1e, Cd14, Ccr5b2, and Mmp9. (F) Gene Ontology enrichment analysis of differentially expressed genes in Operation vs Sham operation (Top 30 GO Terms). (G) GO enrichment comparing SPP1+ Mac vs SPP1– Mac populations. (H) Information flow analysis demonstrating enhanced SPP1 signaling in the Operation group. (I) Gene set enrichment analysis (GSEA) of the ribosome pathway showing significant negative enrichment (NES = –2.74, P = 0.001, FDR = 0.001). (J) Differential number of interactions heatmap across cell types. (K) Cell–cell communication network showing the interaction strength between cell populations. (L) SPP1 signaling pathway network in the Operation and Sham operation groups. (M) UMAP feature plots of SPP1 and Acan expression. (N, O) SPP1 signaling pathway network demonstrating macrophage-nucleus pulposus cell communication.
Cell–cell communication analysis revealed a dominant ligand–receptor circuit centered on SPP1, through which these macrophages impose a catabolic state on NP cells characterized by the downregulation of aggrecan and COL2A1 and the priming of apoptotic pathways. Further analyses showed that these macrophages were associated with pathways involved in inflammation, cellular activation, and tissue remodeling, supporting their contribution to disease progression.
Mechanistically, SPP1 was found to interact directly with major extracellular matrix proteins, and its presence within macrophage-derived exosomes was shown to impair autophagy-lysosome homeostasis in NP cells. Conversely, treatment with exosomes derived from SPP1-knockdown macrophages restored autophagic flux, preserved disc architecture in vivo, and improved histological and micro-CT indicators of degeneration.
Mendelian randomization and genetic colocalization analyses further demonstrated a causal association between elevated SPP1 levels and increased IVDD risk. Analysis of human disc specimens revealed higher SPP1 expression in severely degenerated discs, which positively correlated with disease severity, while independent datasets and machine learning approaches consistently identified SPP1-associated signatures as key predictors of degeneration. Collectively, these findings establish SPP1+ macrophages as central regulators of IVDD and identify osteopontin-mediated immune–matrix interactions as promising therapeutic targets.
In conclusion, this comprehensive multi-omic investigation positions SPP1+ macrophages as critical regulators of immune–matrix interactions during disc degeneration. By establishing SPP1 as a central node linking macrophage activation to matrix degradation, the study provides both a new mechanistic framework for understanding IVDD pathogenesis and a promising translational avenue for clinical intervention. These findings suggest that targeting the SPP1 signaling pathway may offer an effective strategy for mitigating or reversing the pathological processes underlying spinal degeneration.
