title: Acidic pH promotes intervertebral disc degeneration: Acid-sensing ion channel -3 as a potential therapeutic target.
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.
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT UK.|Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PL UK.
authors.forename: Hamish T J
authors.initials: HTJ
authors.lastname: Gilbert
authors.affiliation: Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PL UK.
authors.forename: Nathan
authors.initials: N
authors.lastname: Hodson
authors.affiliation: Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PL UK.
authors.forename: Pauline
authors.initials: P
authors.lastname: Baird
authors.affiliation: Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PL UK.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Richardson
authors.affiliation: Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PL UK.|NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Hoyland
mesh_terms: D062646:Acid Sensing Ion Channel Blockers / Q000494:pharmacology; D062565:Acid Sensing Ion Channels / Q000235:genetics* / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000235:genetics; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D003064:Cnidarian Venoms / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D055959:Intervertebral Disc Degeneration / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D020932:Nerve Growth Factor / Q000096:biosynthesis / Q000235:genetics; D000070614:Nucleus Pulposus / Q000473:pathology; D015533:Transcriptional Activation
chemical_list: C501880:APETx2 protein, Anthopleura elegantissima; C112231:ASIC3 protein, human; D062646:Acid Sensing Ion Channel Blockers; D062565:Acid Sensing Ion Channels; D019208:Brain-Derived Neurotrophic Factor; D003064:Cnidarian Venoms; D016207:Cytokines; C579455:BDNF protein, human; D020932:Nerve Growth Factor