BRD4/MAP2K7/PGF Signaling Axis Promotes Senescence and Extracellular Matrix Metabolism of Nucleus Pulposus Cells in Intervertebral Disk Degeneration.

Abstract

Intervertebral disk degeneration (IDD) is a common age-related degenerative disease of the spine that imposes a substantial economic burden on both families and society. Despite substantial advances in understanding the mechanisms underlying IDD, effective therapeutic interventions for its treatment and prevention remain elusive. Our previous study identified a positive correlation between IDD severity and bromodomain-containing protein 4 (BRD4) expression. However, the multifaceted role of BRD4 in IDD is still not fully understood. This study explored the abnormal elevation of BRD4 expression in nucleus pulposus (NP) tissues from patients with IDD and in an age-related rat model of IDD. We found that BRD4 levels were positively correlated with NP senescence and extracellular matrix (ECM) degradation and inversely correlated with ECM anabolism. These relationships were further confirmed through assays measuring senescence-associated β-galactosidase activity, the expression of senescence markers P21 and P16, senescence-associated secretory phenotype indicators (IL-6, IL-8, MMP3, and MMP13), as well as ECM metabolism markers such as collagen II and aggrecan. Mechanistically, aberrant BRD4 expression was found to upregulate MAP2K7, which in turn enhances PGF expression, promoting NP cell senescence and ECM metabolism. These findings highlight the crucial role of the BRD4/MAP2K7/PGF signaling axis in cellular senescence and ECM regulation, suggesting that BRD4 represents a promising therapeutic target for IDD.