Kingma Sandra D K, Wagemans Tom, IJlst Lodewijk, Wijburg Frits A, van Vlies Naomi
Department of Pediatrics and Amsterdam Lysosome Centre "Sphinx", Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands,
J Inherit Metab Dis. 2014 Sep;37(5):813-21. doi: 10.1007/s10545-014-9703-x. Epub 2014 Apr 4.
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.
I型黏多糖贮积症（MPS I）是一种溶酶体贮积病，其特征在于硫酸乙酰肝素和硫酸皮肤素这两种糖胺聚糖（GAGs）的降解减少，这导致这些GAGs积累并随后引起细胞功能障碍。患者表现出多种症状，包括严重的骨骼疾病。先前已证明染料木黄酮可抑制MPS成纤维细胞中的GAG合成，推测是通过抑制表皮生长因子受体（EGFR）的酪氨酸激酶活性来实现的。为了确定染料木黄酮治疗骨骼疾病的潜力，将MPS I成纤维细胞诱导分化为软骨细胞和成骨细胞，并用染料木黄酮进行处理。令人惊讶的是，尽管所有处理的细胞系中酪氨酸磷酸化水平（作为酪氨酸激酶抑制的指标）均降低，但MPS I软骨细胞和成纤维细胞中的GAG水平分别增加了1.3倍和1.6倍（p <0.05）。处理后的MPS I成纤维细胞中硫酸盐掺入量增加了2.6倍（p <0.05），这表明尽管存在酪氨酸激酶抑制作用，但GAG合成仍增加。这表明GAG合成并非仅通过EGFR的酪氨酸激酶活性进行调节。我们推测，关于染料木黄酮对MPS作用的研究结果存在差异，是由于染料木黄酮对不同生长因子信号通路的不同影响所致，这些信号通路调节GAG合成。需要更多的研究来阐明受染料木黄酮影响并改变GAG代谢的精确信号通路，以便评估染料木黄酮对MPS患者的治疗潜力。
