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.
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.

Reference
Title of the original paper: A Multi-omic atlas identifies osteopontin-expressing macrophages as drivers of intervertebral disc degeneration

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2026.102119

Funding Information:
National Natural Science Foundation of China (No. 82272551)
National Natural Science Foundation of China (No. 81772408)
Graduate Research and Innovation Program of Anhui Medical University (No. YJS20240033)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

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