Do microenvironmental changes in degenerative disc disease reflect in systemic circulation? A proteomic investigation.

The complement system plays a crucial role in immune regulation and inflammation, contributing to intervertebral disc degeneration (IDD) pathogenesis. While tissue-specific complement activation in degenerated discs is well-documented, its systemic expression in degenerative disc disease (DDD) plasma remains unclear. This study employed high-throughput mass spectrometry to analyze the plasma and tissue proteomes of 40 DDD patients, comprising of Modic change (MC) and non-Modic change (NMC) patients, alongside 20 healthy volunteers (HV). Only plasma and no plasma-matched tissue samples were collected from HV group. Proteomic analysis identified 707 proteins in DDD plasma and 655 in HV plasma, with 508 common. Complement and coagulation cascades were enriched, with 46 complement proteins identified. The DDD-plasma group exhibited upregulation of most complement proteins, except for C1q complex (1.38-fold) and Complement Factor D (CFD, 0.64-fold), alongside slight downregulation of vitronectin (VTN), clusterin (CLU), and complement C8G. Elevated C-reactive protein (CRP) levels were observed in DDD-plasma, indicating systemic inflammation. Correlation analysis revealed weak associations between plasma and tissue complement protein levels, suggesting potential regulatory mechanisms. Our study reveals that systemic complement alterations in DDD, supporting their potential as blood-based biomarkers reflecting localized disc pathology. Further validation in larger cohorts across different disease stages is needed to explore their diagnostic and therapeutic implications. Data are available via ProteomeXchange with identifier PXD063403.