miR-4478 Accelerates Nucleus Pulposus Cells Apoptosis Induced by Oxidative Stress by Targeting MTH1

Objectives.Low back pain is the leading cause of disability in the elderly population and is strongly associated with intervertebral disk degeneration (IVDD). However, the precise molecular mechanisms regulating IVDD remain elusive. This study aimed to investigate the role of differentially expressed miRNAs in the pathogenesis of IVDD. Materials and Methods.We analyzed miRNA microarray datasets to identify differentially expressed miRNAs in IVDD progression and conducted quantitative real-time polymerase chain reaction and fluorescence in situ hybridization analysis to further confirm the differential expression of miR-4478 in nucleus pulposus (NP) tissues of patients diagnosed with IVDD. Using public databases of miRNA-mRNA interactions, we predicted the target genes of miR-4478, and subsequent flow cytometry and western blot analyses demonstrated the effect of MTH1 in H2O2-induced nucleus pulposus cells (NPCs) apoptosis. Finally, miR-4478 inhibitor was injected into NP tissues of the IVDD mouse model to explore the effect of miR-4478 in vivo. Results.miR-4478 was upregulated in NP tissues from IVDD patients. Silencing of miR-4478 inhibits H2O2-induced NPCs apoptosis. MTH1 was identified as a target gene for miR-4478, and miR-4478 regulates H2O2-induced NPCs apoptosis by modulating MTH1. In addition, downregulation of miR-4478 alleviated IVDD in a mouse model. Conclusions.In summary, our study provides evidence that miR-4478 may aggravate IVDD through its target gene MTH1 by accelerating oxidative stress in NPCs and demonstrates that miR-4478 has therapeutic potential in IVDD treatment.

Automated summary

This study investigated the role of differentially expressed miRNAs in the pathogenesis of intervertebral disk degeneration (IVDD). The results showed that miR-4478 was upregulated in IVDD patients' nucleus pulposus (NP) tissues. Silencing miR-4478 inhibited hydrogen peroxide (H2O2)-induced nucleus pulposus cells (NPCs) apoptosis. miR-4478 regulated H2O2-induced NPCs apoptosis by modulating MTH1. Furthermore, downregulation of miR-4478 alleviated IVDD symptoms in a mouse model.