White matter extracellular matrix chondroitin sulfate/dermatan sulfate proteoglycans in multiple sclerosis
White matter extracellular matrix chondroitin sulfate/dermatan sulfate proteoglycans in multiple sclerosis
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DOI：
10.1093/jnen/60.12.1198
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发表时间：
2001-12-01
影响因子：
3.2
通讯作者：
Ahmed, AS
中科院分区：
文献类型：
--
作者：
Sobel, RA;Ahmed, AS
多发性硬化症（MS）患者中枢神经系统（CNS）的细胞外基质（ECM）改变是由血脑屏障的破坏、蛋白酶的释放和激活以及ECM成分的合成引起的。为了阐明其潜在的病理生理作用，我们分析了主要的CNS ECM蛋白多糖（pg）在MS和对照CNS组织中的表达。在活跃的MS斑块边缘，3种CNS电凝蛋白（versican， aggrecan和neurocan）和皮肤硫酸酯PG与星形细胞增多有关；在活性斑块中心，它们在ECM中减少，并在泡沫巨噬细胞中积聚，表明这些ECM pg与髓磷脂一起受到损伤并被吞噬。在不活跃的病变中，它们减少了，在正常的白质中，它们显示出迄今为止未被发现的异常异质聚集。磷蛋白，一种在灰质和白质中丰富的ECM PG，变化不太明显。由于在发育过程中，ECM PG的时空表达会影响神经突起的生长、细胞迁移、轴突引导和髓鞘形成，这些数据表明：1)在扩大的病变边缘的促炎环境中，白质卵泡蛋白和皮肤硫酸盐PG表达的增强导致了病变边缘的尖锐和神经元向内生长的失败；2)斑块中心减少可能阻碍再生和修复；3)弥漫性ECM PG损伤与显性病变外的轴突变性有关。因此，ECM PG改变在MS患者中具有特异性、时代性和广泛性，并可能在病变发病机制和中枢神经系统功能障碍中发挥关键作用。
Extracellular matrix (ECM) alterations in the central nervous system (CNS) of multiple sclerosis (MS) patients result from blood-brain barrier breakdown, release and activation of proteases, and synthesis of ECM component,,. To elucidate their potential pathophysiologic roles, we analyzed expression of major CNS ECM proteoglycans (PGs) in MS and control CNS tissues. In active MS plaque edges, 3 CNS lecticans (versican, aggrecan, and neurocan) and dermatan sulfate PG were increased in association with astrocytosis; in active plaque centers they were decreased in the ECM and accumulated in foamy macrophages, suggesting that these ECM PGs are injured and phagocytosed along with myelin. In inactive lesions they were diminished and in normal-appearing white matter they showed heretofore-unappreciated abnormal heterogeneous aggregation. Phosphacan, an ECM PG abundant in both gray and white matter, was less markedly altered. Since in development the spaciotemporal expression of ECM PGs influences neurite outgrowth, cell migration, axon guidance, and myelination, these data suggest that 1) enhanced white matter lectican and dermatan sulfate PG expression in the pro-inflammatory milieu of expanding lesion edges contributes to their sharp boundaries and the failure of neuronal ingrowth; 2) decreases in plaque centers may preclude regeneration and repair; and 3) diffuse ECM PG damage relates to axon degeneration outside of overt lesions. Thus, ECM PG alterations are specific, temporally dynamic, and widespread in MS patients and may play critical roles in lesion pathogenesis and CNS dysfunction.