ASIC1a mediated nucleus pulposus cells pyroptosis and glycolytic crosstalk as a molecular basis for intervertebral disc degeneration

Abstract

Background: One of the etiologic components of degenerative spinal illnesses is intervertebral disc degeneration (IVDD), and the accompanying lower back pain is progressively turning into a significant public health problem. Important pathologic characteristics of IVDD include inflammation and acidic microenvironment, albeit it is unclear how these factors contribute to the disease.

Purpose: To clarify the functions of inflammation and the acidic environment in IVDD, identify the critical connections facilitating glycolytic crosstalk and nucleus pulposus cells (NPCs) pyroptosis, and offer novel approaches to IVDD prevention and therapy.

Methods: By developing keywords search strategy, literature was found and screened using databases such as PUBMED, Google Scholar, Web of Science, China National Knowledge Infrastructure, and others. Hub genes, protein interaction networks, clinical transcriptome data validation, and enrichment analysis were used to further validate relevant biological pathways.

Results: It is clear that disc degeneration is associated with apoptosis or pyroptosis, inflammation, and an acidic environment based on literature review. The process of IVDD is intimately associated with pyroptosis, inflammation, and an acidic environment. The precise mechanism may entail the regulation of key genes such NLRP3, ASIC1a, IL1β, TNF-a, and GSDMD. While the acidic environment exacerbated extracellular matrix degradation and promoted cellular senescence and inflammatory factor expression, it was found to be unfavorable for NPCs survival and proliferation. Moreover, NPCs pyroptosis in an acidic environment, the molecular mechanism behind this phenomenon may be connected to ASIC1a mediated Ca + influx. On the other hand, IVDD can be constantly promoted by the interaction between the degenerating disc's acidic and inflammatory environments through "crosstalk" between anaerobic glycolysis and positive feedback.

Conclusion: In summary, the inflammatory process in NPCs is made worse by the buildup of glucose brought on by metabolic problems, such as anaerobic glycolytic processes, and pyroptosis caused by excessive glucose may be mitigated by inhibiting endoplasmic reticulum stress. A new therapeutic approach for IVDD will involve using ASIC1a as a regulatory target to enhance the inflammatory environment and decrease the incidence of NPCs pyroptosis. Following this, anaerobic glycolysis will be regulated, lactic acid generation will be reduced, and the degenerative vicious loop will be blocked.

Keywords: Acid sensing ion channels; Glycolysis; Inflammation; Intervertebral disk degeneration; Pyroptosis.