Overcoming neurite-inhibitory chondroitin sulfate proteoglycans in the astrocyte matrix
Overcoming neurite-inhibitory chondroitin sulfate proteoglycans in the astrocyte matrix
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DOI：
10.1002/glia.22489
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发表时间：
2013-06-01
期刊：
影响因子：
6.2
通讯作者：
Yong, V. Wee
中科院分区：
文献类型：
--
作者：
Cua, Rowena C.;Lau, Lorraine W.;Yong, V. Wee
中枢神经系统（CNS）的急性创伤可导致与受损轴突再生不良相关的永久性损伤和功能丧失。受损的轴突在再生过程中会遇到一些障碍，比如损伤部位的神经胶质疤痕。胶质瘢痕含有细胞外基质（ECM）大分子，是星形胶质细胞对损伤的反应性沉积。疤痕ECM富含硫酸软骨素蛋白聚糖（CSPGs），这是一种抑制轴突生长的大分子。CSPGs由一个核心蛋白和糖胺聚糖（GAG）链的附着位点组成。大量文献表明，通过软骨素酶ABC去除GAG链允许一些轴突再生；然而，其余完整的核心蛋白也具有抑制结构域。由于金属蛋白酶可以降解CSPG的核心蛋白，我们评估了五种基质金属蛋白酶（MMPs）和一种相关蛋白酶——崩解素和带有血栓反应蛋白基序-4 （ADAMTS-4）的金属蛋白酶——在培养中克服CSPG抑制神经炎生长的能力。选择已知的金属蛋白酶在中枢神经系统损伤后的表达。在MMPs中，MMP-3、-7和-8降低或消除了纯化CSPG底物和星形胶质细胞衍生的ECM上神经突生长的抑制作用。ADAMTS-4还能减弱CSPG对神经突的抑制，并且具有既不降解层粘连蛋白也不引起神经毒性的额外益处。ADAMTS-4的功效与先前报道的阻断介导CSPG抑制的EGFR信号传导相匹配。这些发现强调了ADAMTS-4作为克服CSPG抑制中枢神经系统轴突再生的优越蛋白酶。
Acute trauma to the central nervous system (CNS) can result in permanent damage and loss of function related to the poor regeneration of injured axons. Injured axons encounter several barriers to regeneration, such as the glial scar at the injury site. The glial scar contains extracellular matrix (ECM) macromolecules deposited by reactive astrocytes in response to injury. The scar ECM is rich in chondroitin sulfate proteoglycans (CSPGs), macromolecules that inhibit axonal growth. CSPGs consist of a core protein with attachment sites for glycosaminoglycan (GAG) chains. An extensive literature demonstrates that enzymatic removal of the GAG chains by chondroitinase ABC permits some axonal regrowth; however, the remaining intact core proteins also possess inhibitory domains. Because metalloproteinases can degrade core proteins of CSPGs, we have evaluated five matrix metalloproteinases (MMPs) and a related proteasea disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4)for their capacity to overcome CSPG inhibition of neuritic growth in culture. The metalloproteinases were selected for their known expression after CNS injuries. Of the MMPs, MMP-3, -7 and -8 reduced or abolished inhibition of neurite outgrowth on a purified CSPG substrate and on an astrocyte-derived ECM. ADAMTS-4 also attenuated CSPG inhibition of neurites and had the additional benefits of neither degrading laminin nor causing neurotoxicity. The efficacy of ADAMTS-4 matched that of blocking the EGFR signaling previously reported to mediate CSPG inhibition. These findings highlight ADAMTS-4 as a superior protease for overcoming CSPG inhibition of axonal regeneration in the CNS.