SPP1-CD44 signaling contributes to the mechanisms and therapeutic implications in intervertebral disc degeneration.

BACKGROUND: Intervertebral disc degeneration (IVDD) is a major pathological cause of chronic back pain and reduced mobility. Among emerging molecular regulators, the SPP1-CD44 axis has attracted growing interest for its critical role in immune modulation, cellular migration, and extracellular matrix (ECM) remodeling. SPP1 interacts with CD44 and integrins to regulate immune cell polarization, cytokine secretion, and ECM degradation, ultimately contributing to inflammation, endplate calcification, and disc cell apoptosis. METHODS: This review integrates recent advances in understanding the SPP1-CD44 axis in IVDD. Data were compiled from studies employing single-cell and spatial transcriptomics, immunomodulatory analyses, and experimental or therapeutic interventions, with emphasis on spatiotemporal gene expression, cellular crosstalk, and signaling pathways involving SPP1 and CD44. RESULTS: Recent multi-omics studies reveal dynamic, region-specific expression of SPP1 within the disc microenvironment. Activation of the SPP1-CD44 axis triggers immune and matrix-degrading pathways, facilitating inflammatory cell infiltration. Therapeutic strategies-such as monoclonal antibodies, small-molecule inhibitors, and exosome-based delivery systems-have shown potential to modulate this axis and mitigate disc degeneration. CONCLUSION: The SPP1-CD44 axis represents a central regulatory mechanism in IVDD pathogenesis. Targeting this pathway may offer novel therapeutic avenues. Integration of artificial intelligence with multi-omics modeling could further enable precision-guided, personalized interventions. Continued mechanistic exploration of this axis will be crucial for developing innovative therapies that transcend the limitations of conventional treatments and improve patient outcomes.