Apoptosis Signal-Regulated Kinase-1 Promotes Nucleus Pulposus Cell Senescence and Apoptosis to Regulate Intervertebral Disc Degeneration

Abstract

This study investigated the role of apoptosis signal-regulated kinase-1 (ASK1) in intervertebral disc degeneration (IDD). The nucleus pulposus (NP) tissues of non-IDD and IDD patients were subjected to hematoxylin and eosin, Safranin O–fast green, and immunohistochemical staining. Quantitative real-time PCR was used to assess the ASK1 mRNA level within NP tissue samples and cells. The Cell Counting Kit-8 assay, senescence-associated β-galactosidase staining, and flow cytometry were conducted to assess the viability, senescence, and apoptosis of NP cells, respectively. Extracellular matrix–related factors were detected using Western blot analysis. Furthermore, the effect of ASK1 on the IDD rat model was evaluated. Finally, c-Jun N-terminal kinase (JNK) inhibitors were used to verify the effect of the JNK/p38 signaling on IDD. ASK1 mRNA and protein were up-regulated within NP tissue samples from the IDD group, IL-1β–stimulated NP cells, and IDD rats. ASK1 inhibition promoted cell viability and repressed the senescence and apoptosis of NP cells, promoted collagen II and aggrecan, inhibited matrix metalloproteinase 3/9 and a disintegrin and metalloproteinase with thrombospondin motifs 4/5 protein levels, and increased NP cells in rat intervertebral disc tissues. ASK1 overexpression exerted the opposite effects of ASK1 inhibition on NP cells. Additionally, JNK/p38 signaling suppression could reverse the ASK1 up-regulation–induced dysfunction. In conclusion, ASK1 facilitated the senescence and apoptosis of NP cells in promoting IDD progression via the JNK/p38 pathway.