A Multi-omic atlas identifies osteopontin-expressing macrophages as drivers of intervertebral disc degeneration

Intervertebral disc degeneration (IVDD) lacks disease-modifying therapies, in part because immune drivers of matrix failure remain poorly defined. Here, we built a multi-omic framework integrating single-cell RNA-seq of rat discs, cell–cell communication inference, exosome biology, machine learning prioritization, and two-sample Mendelian randomization (MR). Across degenerating discs, we identified an expanded SPP1 + (osteopontin) macrophage population that spatially neighbors and transcriptionally interacts with nucleus pulposus (NP) cells through a ligand–receptor circuit centered on SPP1. Exosomes from SPP1 + macrophages impose a catabolic NP state characterized by aggrecan loss, COL2A1 down-regulation and apoptosis priming, whereas exosomes from SPP1-silenced macrophages reverse these programs and attenuate matrix degradation. In a pressure-induced rat IVDD model, delivery of SPP1-knockdown macrophage exosomes preserves disc architecture and improves histologic and micro-CT indices. Causal inference using pQTL-anchored MR supports a directional effect of circulating SPP1 on IVDD risk (OR = 1.15, 95% CI 1.08–1.23, P = 0.001), robust to pleiotropy and heterogeneity tests, with colocalization analysis confirming shared genetic signals (PP.H4 = 0.78). Human IVD specimens validate elevated SPP1 expression in degenerated discs correlating with Pfirrmann grade. A supervised learning pipeline converges on SPP1/CD86 modules as top features predicting degenerative states across datasets. These convergent analyses position SPP1 + macrophages as organizers of an immune-matrix axis in IVDD and nominate exosome-directed SPP1 blockade as a tractable therapeutic strategy.