Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.6.1 (sulfatase)
 3,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Regional differences in retinal pigment epithelial (RPE) cell glycosaminoglycan (GAG) and collagen metabolism were studied using cells obtained from normal cats and those with deficient activity of arylsulfatase B (ASB), a lysosomal enzyme involved in GAG catabolism. Control and ASB-deficient RPE cultures initiated from superior equatorial (superior) and inferior equatorial (inferior) regions of the eye were radiolabeled for 72 hr with 35SO4, and GAGs from the media and cell layers were analyzed separately. In ASB-deficient RPE, there was an accumulation of dermatan/chondroitin sulfate in the cell layer of cultures initiated from the superior region of the eye but not in those initiated from the inferior region. This agrees with previous in situ and in vitro morphologic observations that accumulation of inclusions in ASB-deficient RPE was greater in the superior region of the eye than in the inferior region. By contrast, media from ASB-deficient cultures initiated from the inferior region of the eye contained much higher levels of radiolabeled dermatan/chondroitin sulfate than ASB-deficient cultures from the superior region or normal cultures. Increased GAG content in the media may result from increased secretion of proteoglycans, increased turnover of cell surface or extracellular matrix components, or extrusion of lysosomal contents. These results indicate that one or more of these mechanisms vary regionally throughout the eye in the RPE of ASB-deficient animals. Collagen production was determined in normal and ASB-deficient RPE cultures. In normal RPE, no differences in collagen synthesis were noted between the inferior and superior regions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glycosaminoglycan and collagen metabolism in arylsulfatase B-deficient retinal pigment epithelium in vitro. 190 76

Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is a lysosomal storage disorder caused by deficiency of N-acetylgalactosamine-6-sulfatase (GALNS), an enzyme that degrades keratan sulfate (KS). Currently no therapy for MPS IVA is available. We produced recombinant human (rh)GALNS as a potential enzyme replacement therapy for MPS IVA. Chinese hamster ovary cells stably overexpressing GALNS and sulfatase modifying factor-1 were used to produce active ( approximately 2 U/mg) and pure (>or=97%) rhGALNS. The recombinant enzyme was phosphorylated and was dose-dependently taken up by mannose-6-phosphate receptor (K(uptake) = 2.5 nM), thereby restoring enzyme activity in MPS IVA fibroblasts. In the absence of an animal model with a skeletal phenotype, we established chondrocytes isolated from two MPS IVA patients as a disease model in vitro. MPS IVA chondrocyte GALNS activity was not detectable and the cells exhibited KS storage up to 11-fold higher than unaffected chondrocytes. MPS IVA chondrocytes internalized rhGALNS into lysosomes, resulting in normalization of enzyme activity and decrease in KS storage. rhGALNS treatment also modulated gene expression, increasing expression of chondrogenic genes Collagen II, Collagen X, Aggrecan and Sox9 and decreasing abnormal expression of Collagen I. Intravenous administration of rhGALNS resulted in biodistribution throughout all layers of the heart valve and the entire thickness of the growth plate in wild-type mice. We show that enzyme replacement therapy with recombinant human GALNS results in clearance of keratan sulfate accumulation, and that such treatment ameliorates aberrant gene expression in human chondrocytes in vitro. Penetration of the therapeutic enzyme throughout poorly vascularized, but clinically relevant tissues, including growth plate cartilage and heart valve, as well as macrophages and hepatocytes in wild-type mouse, further supports development of rhGALNS as enzyme replacement therapy for MPS IVA.
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PMID:Enzyme replacement in a human model of mucopolysaccharidosis IVA in vitro and its biodistribution in the cartilage of wild type mice. 2080 38