Impairment of the activity of glycosaminoglycan-binding cytokines by functionally abnormal heparan sulfates: a novel mechanism underlying disease pathophysiology.
Impairment of the activity of glycosaminoglycan-binding cytokines by functionally abnormal heparan sulfates: a novel mechanism underlying disease pathophysiology.
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DOI：
10.1100/tsw.2006.83
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发表时间：
2006-04-05
影响因子：
--
通讯作者：
Gupta P
中科院分区：
文献类型：
--
作者：
Gupta P
In Hurler syndrome (mucopolysaccharidosis-I; MPS-I, the most common MPS disorder), an inborn deficiency of the lysosomal hydrolase α-L-iduronidase (IDUA) leads to incomplete degradation and lysosomal accumulation of heparan sulfate (HS) and dermatan sulfate (DS) glycosaminoglycans (GAGs; Fig. 1)[1]. The mechanisms by which accumulated GAGs cause multiorgan dysfunction, including the devastating neuropsychological manifestations of Hurler syndrome and other mucopolysaccharidoses, remain unclear. The neuropathology of Hurler syndrome includes neuronal loss leading to brain atrophy and formation of ectopic dendrites and synapses [2, 3]. These features cannot be explained simply by the mechanical effect of GAG-distended lysosomes. It is well known that the fibroblast growth factor (FGF) cytokine family mediates cell growth and differentiation, as well as neurogenesis, axonal guidance, and neuronal survival [4, 5, 6]. The interaction of HS with FGF2 and its effect on the biological activity of FGF2 have been studied extensively [7]. In normal cells, structurally specific HS is required for optimal biological activity of FGF2 [8], by formation of the “FGF2-FGF-receptor-HS” complex [9, 10]. One structural feature required for facilitation of FGF2 activity is 6-O-sulfation of HS [11, 12]. However, the consequences of structurally abnormal HS in a disease state on FGF2 activity and their contribution to disease pathophysiology have not been defined. We hypothesized that the functional properties of the abnormal-sized and sulfated HS in Hurler syndrome are defective, and that this leads to aberrant modulation of the biological activity of GAG-binding cytokines such as the FGFs, thereby contributing to the pathophysiology of Hurler syndrome (Fig. 2). Until recently, a major impediment to examining the developmental role of HS in vitro has been the lack of primary progenitor cells capable of differentiation into neuronal and other cell types representative of tissues affected by Hurler syndrome. This limitation has been removed by a major advance in cell biology: the isolation and culture of a multipotent, nonhematopoietic stem cell from human and rodent bone marrow (the multipotent adult progenitor cell: MAPC) capable of extensive expansion, and in vitro and in vivo differentiation into endodermal, mesodermal, and neuroectodermal cells representing all three embryonic lineages [13, 14, 15]. MAPCs,
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影响因子：
20.3
作者：
Pan, CD;Nelson, MS;Gupta, P
通讯作者：
Gupta, P
影响因子：
4.8
作者：
Pye, DA;Vives, RR;Gallagher, JT
通讯作者：
Gallagher, JT
影响因子：
2.9
作者：
Krufka, A;Guimond, S;Rapraeger, AC
通讯作者：
Rapraeger, AC
影响因子：
64.5
作者：
YAYON, A;KLAGSBRUN, M;ORNITZ, DM
通讯作者：
ORNITZ, DM
影响因子：
4.8
作者：
Chang, Z;Meyer, K;Friedl, A
通讯作者：
Friedl, A