Abstract
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.
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Acknowledgments
We thank Rene Leen, Vincent Everts, Henk van Lenthe, Wim Kulik and Ronald Wanders for technical assistance and helpful discussions. We thank Gregorz Węgrzyn for kindly providing the protocol for sulfate incorporation and helpful discussions and Axcentua for providing genistein. This work was funded by the WE foundation and the foundation ‘Steun Emma Kinderziekenhuis AMC’.
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Sandra Kingma, Tom Wagemans, Lodewijk IJlst, Frits Wijburg and Naomi van Vlies declare that they have no conflicts of interest.
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Informed consent for the use of fibroblast cell lines was obtained from all patients or parents of the patients. Apart from experiments using these cell lines, this article does not contain any studies with human or animal subjects performed by the any of the authors.
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Communicated by: Alberto B. Burlina
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Kingma, S.D.K., Wagemans, T., IJlst, L. et al. Genistein increases glycosaminoglycan levels in mucopolysaccharidosis type I cell models. J Inherit Metab Dis 37, 813–821 (2014). https://doi.org/10.1007/s10545-014-9703-x
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DOI: https://doi.org/10.1007/s10545-014-9703-x