Wg. Hill et al., ORGAN-SPECIFIC OVER-SULFATION OF GLYCOSAMINOGLYCANS AND ALTERED EXTRACELLULAR-MATRIX IN A MOUSE MODEL OF CYSTIC-FIBROSIS, Biochemical and molecular medicine, 62(1), 1997, pp. 113-122
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.