LRP1 mitigates intervertebral disc degeneration by inhibiting endoplasmic reticulum stress through stabilizing the PPARγ.

Background: Intervertebral disc degeneration (IDD) is a significant cause of lower back pain, characterized by inflammation-mediated extracellular matrix (ECM) degradation, apoptosis, and aging of nucleus pulposus (NP) cells. Identifying key regulatory targets for these processes is crucial for IDD treatment. Previous research has highlighted the role of low-density lipoprotein receptor-related protein 1 (LRP1) in regulating ECM levels and cell fate, but its role in IDD remains under-explored. This study aims to elucidate the function and mechanism of LRP1 in the progression of IDD. Methods: LRP1 expression was assessed in clinical tissue samples from patients diagnosed with IDD and in a rat IDD model established using needle puncture injuries. The effects of LRP1 knockdown and treatment with the LRP1 activator SP16 on apoptosis and ECM metabolism in NP cells were analyzed, with a focus on their relationship with endoplasmic reticulum (ER) stress. The interaction and regulatory mechanism between LRP1 and peroxisome proliferator-activated receptor gamma (PPARγ) were further explored to clarify how LRP1 regulates ER stress. Finally, the in vivo therapeutic effect of SP16 was investigated using a rat tail IDD model. Results: We found that LRP1 expression was significantly downregulated in IDD. In NP cells with LRP1 knockdown, there was a marked increase in apoptosis and detrimental ECM remodeling, which were associated with the activation of ER stress. Our research further revealed that LRP1 interacts with PPARγ, stabilizing the PPARγ protein and preventing its lysosomal degradation, thereby mitigating ER stress. Activation of LRP1 in our models significantly reduced ER stress, matrix degradation, and apoptosis, thereby attenuating IDD both in vitro and in vivo. Conclusion: This study systematically investigated the role and mechanisms of the LRP1/PPARγ/ER stress signaling axis in IDD. Our findings suggest that targeting LRP1 to modulate this signaling pathway could provide a promising therapeutic approach for the treatment of IDD. The Translational potential of this Article: Our study demonstrated that LRP1 can reduce apoptosis and ECM degradation by inhibiting ER stress through stabilizing PPARγ, indicating that targeting LRP1 may be a novel therapeutic strategy for IDD.