Acidic pH promotes intervertebral disc degeneration: Acid-sensing ion channel -3 as a potential therapeutic target

Sci Rep. 2016 Nov 17:6:37360. doi: 10.1038/srep37360.

Abstract

The aetiology of intervertebral disc (IVD) degeneration remains poorly understood. Painful IVD degeneration is associated with an acidic intradiscal pH but the response of NP cells to this aberrant microenvironmental factor remains to be fully characterised. The aim here was to address the hypothesis that acidic pH, similar to that found in degenerate IVDs, leads to the altered cell/functional phenotype observed during IVD degeneration, and to investigate the involvement of acid-sensing ion channel (ASIC) -3 in the response. Human NP cells were treated with a range of pH, from that of a non-degenerate (pH 7.4 and 7.1) through to mildly degenerate (pH 6.8) and severely degenerate IVD (pH 6.5 and 6.2). Increasing acidity of pH caused a decrease in cell proliferation and viability, a shift towards matrix catabolism and increased expression of proinflammatory cytokines and pain-related factors. Acidic pH resulted in an increase in ASIC-3 expression. Importantly, inhibition of ASIC-3 prevented the acidic pH induced proinflammatory and pain-related phenotype in NP cells. Acidic pH causes a catabolic and degenerate phenotype in NP cells which is inhibited by blocking ASIC-3 activity, suggesting that this may be a useful therapeutic target for treatment of IVD degeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Sensing Ion Channel Blockers / pharmacology
  • Acid Sensing Ion Channels / genetics*
  • Acid Sensing Ion Channels / metabolism
  • Brain-Derived Neurotrophic Factor / biosynthesis
  • Brain-Derived Neurotrophic Factor / genetics
  • Cell Proliferation
  • Cell Survival
  • Cells, Cultured
  • Cnidarian Venoms / pharmacology
  • Cytokines / biosynthesis
  • Cytokines / genetics
  • Drug Evaluation, Preclinical
  • Female
  • Humans
  • Hydrogen-Ion Concentration
  • Intervertebral Disc Degeneration / drug therapy
  • Intervertebral Disc Degeneration / metabolism*
  • Male
  • Middle Aged
  • Molecular Targeted Therapy
  • Nerve Growth Factor / biosynthesis
  • Nerve Growth Factor / genetics
  • Nucleus Pulposus / pathology
  • Transcriptional Activation

Substances

  • APETx2 protein, Anthopleura elegantissima
  • ASIC3 protein, human
  • Acid Sensing Ion Channel Blockers
  • Acid Sensing Ion Channels
  • Brain-Derived Neurotrophic Factor
  • Cnidarian Venoms
  • Cytokines
  • BDNF protein, human
  • Nerve Growth Factor