HMGB1-mediated macrophage regulation of NF-κB activation and MMP3 upregulation in nucleus pulposus cells: A critical mechanism in the vicious cycle of intervertebral disc degeneration.

Intervertebral disc degeneration (IVDD) is a leading cause of low back pain, primarily driven by inflammatory processes within the disc, particularly involving the infiltration and activity of macrophages. High Mobility Group Box 1 (HMGB1) has been identified as a crucial mediator in this inflammatory cascade, yet its precise role in macrophage-induced disc degeneration remains unclear. In this study, we employed a combination of in vivo and in vitro models, including genetically engineered mice with macrophage-specific overexpression of HMGB1, a rat model of IVDD, and cultured macrophages and nucleus pulposus cells (NPCs), to elucidate the role of HMGB1 in IVDD. Our findings reveal that HMGB1 overexpression in macrophages significantly accelerates IVDD progression by enhancing NF-κB activation and upregulating MMP3 expression in NPCs. Furthermore, the administration of glycyrrhizin (GL), an HMGB1 inhibitor, effectively mitigated these effects, delaying IVDD progression. This study not only uncovers the critical mechanisms by which HMGB1 regulates the interactions between macrophages and NPCs in the inflammatory microenvironment but also provides a theoretical framework for targeting HMGB1 as a potential therapeutic strategy for IVDD. Thus, our findings suggest a promising novel approach for the treatment of this condition.