Hotchkiss Brain Institute and the Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.
Glia. 2013 Jun;61(6):972-84. doi: 10.1002/glia.22489. Epub 2013 Mar 28.
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 protease-a 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.
中枢神经系统（CNS）的急性创伤可导致与受伤轴突再生不良相关的永久性损伤和功能丧失。受伤的轴突在再生过程中会遇到多种障碍，例如损伤部位的神经胶质瘢痕。神经胶质瘢痕含有细胞外基质（ECM）大分子，这些大分子是反应性星形胶质细胞在受伤后沉积的。瘢痕 ECM 富含软骨素硫酸盐蛋白聚糖（CSPG），这是一种抑制轴突生长的大分子。CSPG 由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 链可以促进一些轴突再生；然而，剩余完整的核心蛋白也具有抑制域。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）和一种相关的蛋白酶-解整合素和金属蛋白酶 4（ADAMTS-4），以评估它们在体外克服 CSPG 抑制神经突生长的能力。选择这些金属蛋白酶是因为它们在中枢神经系统损伤后已知表达。在 MMPs 中，MMP-3、-7 和 -8 减少或消除了对纯化的 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 也减弱了 CSPG 对神经突的抑制作用，并且没有降解层粘连蛋白或引起神经毒性的额外好处。ADAMTS-4 的功效与之前报道的阻断 EGFR 信号通路以介导 CSPG 抑制的功效相匹配。这些发现突出了 ADAMTS-4 作为一种优越的蛋白酶，可以克服中枢神经系统中 CSPG 对轴突再生的抑制作用。
