Genistein increases glycosaminoglycan levels in mucopolysaccharidosis type I cell models.
Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder characterized by diminished degradation of the glycosaminoglycans (GAGs) heparan sulfate and dermatan sulfate, which results in the accumulation of these GAGs and subsequent cellular dysfunction. Patients present with a variety of symptoms, including severe skeletal disease. Genistein has been shown previously to inhibit GAG synthesis in MPS fibroblasts, presumably through inhibition of tyrosine kinase activity of the epidermal growth factor receptor (EGFR). To determine the potentials of genistein for the treatment of skeletal disease, MPS I fibroblasts were induced into chondrocytes and osteoblasts and treated with genistein. Surprisingly, whereas tyrosine phosphorylation levels (as a measure for tyrosine kinase inhibition) were decreased in all treated cell lines, there was a 1.3 and 1.6 fold increase in GAG levels in MPS I chondrocytes and fibroblast, respectively (p < 0.05). Sulfate incorporation in treated MPS I fibroblasts was 2.6 fold increased (p < 0.05), indicating increased GAG synthesis despite tyrosine kinase inhibition. This suggests that GAG synthesis is not exclusively regulated through the tyrosine kinase activity of the EGFR. We hypothesize that the differences in outcomes between studies on the effect of genistein in MPS are caused by the different effects of genistein on different growth factor signaling pathways, which regulate GAG synthesis. More studies are needed to elucidate the precise signaling pathways which are affected by genistein and alter GAG metabolism in order to evaluate the therapeutic potential of genistein for MPS patients.
Department of Pediatrics and Amsterdam Lysosome Centre "Sphinx", Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, s.d.kingma@amc.uva.nl.
Sandra D K
SD
Kingma
Tom
T
Wagemans
Lodewijk
L
IJlst
Frits A
FA
Wijburg
Naomi
N
van Vlies
D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019833:Genistein / Q000494:pharmacology*; D006025:Glycosaminoglycans / Q000378:metabolism*; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology; D008059:Mucopolysaccharidosis I / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D013431:Sulfates / Q000378:metabolism
D004791:Enzyme Inhibitors; D006025:Glycosaminoglycans; D007529:Isoflavones; D013431:Sulfates; D019833:Genistein