Sumit Bhattacharyya1, Leo Feferman1, Girish Sharma2, Joanne K Tobacman3. 1. Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA; Jesse Brown VAMC, Chicago, IL, 60612, USA. 2. Department of Pediatrics, Rush University Medical Center, Chicago, IL 60612, USA. 3. Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA; Jesse Brown VAMC, Chicago, IL, 60612, USA. Electronic address: jkt@uic.edu.
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. Published by Elsevier Inc.
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. Published by Elsevier Inc.