Upregulation of glycosaminoglycan synthesis by Neurotropin in nucleus pulposus cells via stimulation of chondroitin sulfate N-acetylgalactosaminyltransferase 1: A new approach to attenuation of intervertebral disc degeneration

PLoS One. 2018 Aug 27;13(8):e0202640. doi: 10.1371/journal.pone.0202640. eCollection 2018.

Abstract

It is suggested that most cases of low back pain are related to degeneration of intervertebral discs. Disc degeneration is a chronic and progressive disease and the search for effective medical treatments continues. Neurotropin is widely used in Japan and China to treat low back pain and neck-shoulder-arm syndrome. The present study aimed to investigate the effect of Neurotropin on glycosaminoglycan synthesis in nucleus pulposus cells. Cultured human nucleus pulposus cells were treated with Neurotropin every second day for two weeks. Production of glycosaminoglycan was assessed using a dimethyl-methylene blue assay and PicoGreen was used to measure DNA content. Microarray analysis, real-time PCR, and western blotting were performed to assess the biological processes related to Neurotropin-stimulated glycosaminoglycan synthesis. The results showed that the level of glycosaminoglycan normalized to DNA content was significantly upregulated by the addition of Neurotropin. Gene expression profiling showed over two-fold upregulation of 697 genes in response to Neurotropin treatment. Among these genes, ontological analysis suggested significant implication of phosphatidylinositol 3-kinase signaling, and analysis focused on this pathway demonstrated marked upregulation of angiopoietin 1 and insulin-like growth factor 1. Activation of phosphorylation of the signal transducer protein AKT was detected by western blotting. Of the genes related to sulfated glycosaminoglycan synthesis, the greatest increase in mRNA levels was observed for chondroitin sulfate N-acetylgalactosaminyltransferase 1, an enzyme initiating synthesis of chondroitin sulfate side chains attached to a core protein of aggrecan, which is a predominant disc matrix component. These findings suggest that Neurotropin may activate the phosphatidylinositol 3-kinase-AKT pathway and stimulate glycosaminoglycan synthesis through upregulation of expression of mRNA for chondroitin sulfate N-acetylgalactosaminyltransferase 1. Because there was no cytotoxic cellular growth inhibition, Neurotropin treatment might offer an accessible therapeutic strategy for intervertebral disc degeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Angiopoietin-1 / genetics
  • Cell Proliferation / drug effects
  • Female
  • Gene Expression Profiling
  • Glycosaminoglycans / biosynthesis*
  • Glycosaminoglycans / genetics
  • Humans
  • Insulin-Like Growth Factor I / genetics
  • Intervertebral Disc Degeneration / drug therapy
  • Intervertebral Disc Degeneration / genetics*
  • Intervertebral Disc Degeneration / physiopathology
  • Male
  • N-Acetylgalactosaminyltransferases / genetics*
  • Nucleus Pulposus / drug effects
  • Nucleus Pulposus / metabolism
  • Polysaccharides / administration & dosage*
  • Primary Cell Culture
  • Proto-Oncogene Proteins c-akt / genetics

Substances

  • Angiopoietin-1
  • Glycosaminoglycans
  • Polysaccharides
  • neurotropin
  • Insulin-Like Growth Factor I
  • N-Acetylgalactosaminyltransferases
  • chondroitin sulfate N-acetylgalactosaminyltransferase-1
  • Proto-Oncogene Proteins c-akt

Grants and funding

The authors received a research grant from Nippon Zoki Pharmaceutical Company Ltd. (http://www.nippon-zoki.co.jp/). The funder provided support in the form of a salary for an author TN and contributed to decision to publish this work. The specific role of the author is articulated in the author contributions section.