Inhibition of TrkB-BDNF positive feedback loop attenuates intervertebral disc degeneration and low back pain in a composite mouse model.

Intervertebral disc degeneration (IVDD) is a significant contributor to low back pain (LBP); however, the specific mechanisms involved remain unclear. Herein, a novel LBP mouse model was developed by integrating a bipedal standing model with a lumbar spine instability model (BS + LSI). This model effectively reproduced the behavioral characteristics of LBP and the pathological features of IVDD. Notably, a higher degree of degeneration and innervation in the endplates were observed in the BS + LSI mice. Transcriptome analysis revealed a significant upregulation of Ntrk2, the gene encoding TrkB, in the intervertebral discs of BS + LSI mice. Immunohistochemical staining further confirmed elevated expression of TrkB and its ligand BDNF in the endplates of these mice. Moreover, cyclic tensile strain (CTS) (20 %, 0.1 Hz, 24 h) upregulated TrkB expression and activated NF-κB signaling pathway to promote inflammatory responses in endplate chondrocytes. siBDNF transfection or treatment with the TrkB inhibitor ANA-12 effectively inhibited these pathological changes. Mechanistically, TrkB promoted BDNF expression by enhancing CREB phosphorylation, thereby establishing a TrkB-CREB-BDNF positive feedback loop. In vivo injection of ANA-12 significantly alleviated endplate inflammation and LBP-related behaviors in BS + LSI mice. Thus, an effective and replicable mouse model of LBP was established to identify TrkB as both the receptor for and an upstream regulator of BDNF, making it a crucial target for interventions to alleviate CEP inflammation and LBP.