Increased GPNMB, phospho-ERK1/2, and MMP-9 in cystic fibrosis in association with reduced arylsulfatase B

Mol Genet Metab. 2018 Jun;124(2):168-175. doi: 10.1016/j.ymgme.2018.02.012. Epub 2018 Feb 20.

Abstract

Background: GPNMB was increased in a CF gene array and in Arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase)-null mice, consistent with previous reports that ARSB is reduced in cystic fibrosis (CF). Implications of GPNMB increase in CF are unknown.

Methods: GPNMB levels were determined in serum and circulating leukocytes from CF patients and healthy controls. GPNMB binding with β-1 integrin and measurements of phospho-ERK1/2 and MMP-9 in CFTR-uncorrected, CFTR-corrected, and normal human bronchial epithelial cells (BEC) were determined, following ARSB and GPNMB knockdown, and treatment with RGD peptide, and ERK phosphorylation inhibitor.

Results: GPNMB was markedly increased in CF patients compared to controls (p < 0.0001, unpaired t-test, two-tailed). Silencing GPNMB, treatment with excess RGD peptide, and treatment with ERK phosphorylation inhibitor blocked ARSB silencing-induced increases in MMP-9 in the normal BEC.

Conclusions: Findings suggest that decline in ARSB activity caused by decline in CFTR function leads to increased GPNMB, which may contribute to organ dysfunction in CF by increased MMP-9 expression.

Keywords: Glycosaminoglycans; N-acetylgalactosamine-4-sulfatase; Sulfatase; β-1 integrin.

MeSH terms

  • Adolescent
  • Adult
  • Biomarkers / metabolism*
  • Bronchi / cytology
  • Bronchi / metabolism
  • Case-Control Studies
  • Cells, Cultured
  • Child
  • Cystic Fibrosis / metabolism*
  • Cystic Fibrosis / pathology*
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Female
  • Humans
  • Male
  • Matrix Metalloproteinase 9 / metabolism*
  • Membrane Glycoproteins / metabolism*
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • N-Acetylgalactosamine-4-Sulfatase / metabolism*
  • Phosphorylation
  • Young Adult

Substances

  • Biomarkers
  • GPNMB protein, human
  • Membrane Glycoproteins
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • N-Acetylgalactosamine-4-Sulfatase
  • ARSB protein, human
  • MMP9 protein, human
  • Matrix Metalloproteinase 9