A Network‐Based Approach to Understanding Key Signaling Pathways in Intervertebral Disc Biology

ABSTRACT Background Intervertebral disc degeneration (IDD) reflects a poorly characterized shift from anabolic matrix renewal to catabolic breakdown. Fragmentary experimental and modeling efforts leave many signaling routes unresolved; a consolidated map is required to guide hypothesis‐driven studies. Methods A literature‐curated regulatory network model (RNM) for human nucleus pulposus (NP) cells was assembled from PubMed and enriched with interactions from STRING, KEGG and R&D Systems. The static graph was converted to a semi‐quantitative dynamical system. Simulations examined responses to interleukin‐1β (IL‐1β) and the Toll‐like receptor (TLR) and were benchmarked against time‐resolved proteomics from 2D NP monolayers and 3D alginate cultures representing healthy and degenerated discs. Single‐node perturbations assessed the impact of targeted inhibition on catabolic output. Results The final network contains 82 proteins and 193 directed edges; 41.4% of supporting evidence derives from NP‐specific studies, the highest for any cell type. Baseline activity depicts a non‐degenerate disc, with high expression of anabolic mediators and low expression of catabolic enzymes. Both IL‐1β and TLR elicited strong c‐Jun and p65 NF‐κB activation in silico and in vitro. The model simulated IκBα depletion, whereas its increase in the experimental study shows the biological agreement among in silico and in vitro simulations. Conclusions This RNM unifies scattered IDD data into a validated dynamic framework that mirrors NP signaling. The publicly available model provides a foundation for multiscale studies linking molecular events to disc mechanics and for prioritizing therapeutic interventions.