ORGAN-SPECIFIC OVER-SULFATION OF GLYCOSAMINOGLYCANS AND ALTERED EXTRACELLULAR-MATRIX IN A MOUSE MODEL OF CYSTIC-FIBROSIS

Cystic fibrosis (CF) is a fatal inherited disease caused by the loss o f function of a plasma membrane chloride channel-the cystic fibrosis t ransmembrane conductance regulator (CFTR), It is characterized by visc ous mucous secretions which have abnormal glycosylation and sulfation, The development of a CFTR knockout mouse has allowed in vivo experime nts aimed at investigating the over-sulfation phenomenon reported for CF glycoconjugates, Four CF and five control mice injected with [S-35] sulfate were examined for differences in the sulfation of glycosaminog lycans (GAGs) synthesized by 12 tissues after 48 h. The liver and panc reas of CF mice incorporated significantly higher amounts of [(35)]sul fate into GAGs (dpm/mu g) than the controls, while the ileum, jejunum, colon, cecum, spleen, trachea, and gall bladder of CF mice exhibited higher incorporation levels that were not significant. The lung and na sal septum were not different, and the nasal mucosa of CF mice was sig nificantly lower (P < 0.05). Structural analysis of the chondroitin/de rmatan sulfate component by strong anion-exchange HPLC revealed that t he liver and ileum of CF mice incorporated significantly more total su lfate than controls. However, for other organs, the explanation for hi gher isotope incorporation was a 40-50% higher specific activity of [S -35]sulfate within GAGs, This finding implied different uptake kinetic s of sulfate from the circulation or that CF mice have altered sulfate pools. CF mice also had altered proportions of chondroitin/dermatan s ulfate to heparan sulfate in the ileum and gall bladder (P < 0.05). We conclude that extracellular matrix architecture in some CF organs may be abnormal and that sulfation of glycoconjugates by some organs and sulfate utilization in others have been affected by the loss of CFTR, This study provides the first in vivo evidence for an influence of CFT R on glycoconjugate sulfation and suggests other secondary manifestati ons of CFTR dysfunction associated with abnormalities of the extracell ular matrix. (C) 1997 Academic Press.