Abstract

Intervertebral disc degeneration (IDD) arises from an intricate imbalance between the anabolic and catabolic processes governing the extracellular matrix (ECM) within the disc. Biochemical processes are complex, redundant and feedback-looped, thus improved integration of knowledge is needed. To address this, a literature-based regulatory network model (RNM) for nucleus pulposus cells (NPC) is proposed, representing the normal state of the intervertebral disc (IVD) cells, in which proteins are represented by nodes that interact with each other through activation and/or inhibition edges.

This model includes 32 different proteins and 150 edges by incorporating critical biochemical interactions in IVD regulation, tested in vivo or in vitro in human and animal NPC, alongside non-tissue-specific protein-protein interactions. We used the network to calculate the dynamic regulation of each node through a semi-quantitative method. The basal steady state successfully represented the activity of a normal NPC, and the model was assessed through the published literature, by replicating two independent experimental studies in human normal NPC.

Pro-catabolic or pro-anabolic shifts of the network activated by nodal perturbations could be predicted. Sensitivity analysis underscored the significant influence of transforming growth factor beta (TGF-β) and interleukin-1 receptor antagonist (IL-1Ra) on the regulation of structural proteins and degrading enzymes within the system. Given the ongoing challenge of elucidating the mechanisms that drive ECM degradation in IDD, this unique IVD RNM holds promise as a tool for exploring and predicting IDD progression, shedding light on IVD phenotypes and guiding experimental research efforts.