Overcoming neurite-inhibitory chondroitin sulfate proteoglycans in the astrocyte matrix

被引:77
作者
Cua, Rowena C. [1 ,2 ]
Lau, Lorraine W. [1 ,2 ]
Keough, Michael B. [1 ,2 ]
Midha, Rajiv [1 ,2 ]
Apte, Suneel S. [3 ]
Yong, V. Wee [1 ,2 ]
机构
[1] Univ Calgary, Hotchkiss Brain Inst, Calgary, AB T2N 4N1, Canada
[2] Univ Calgary, Dept Clin Neurosci, Calgary, AB T2N 4N1, Canada
[3] Cleveland Clin Fdn, Dept Biomed Engn, Lerner Res Inst, Cleveland, OH 44195 USA
关键词
axonal regeneration; extracellular matrix; MMPs; neurons; proteases; SPINAL-CORD-INJURY; CENTRAL-NERVOUS-SYSTEM; PROMOTES FUNCTIONAL RECOVERY; MULTIPLE-SCLEROSIS; AXON REGENERATION; WHITE-MATTER; CNS INJURY; METALLOPROTEINASE INHIBITORS; INTRACEREBRAL HEMORRHAGE; EXTRACELLULAR-MATRIX;
D O I
10.1002/glia.22489
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:972 / 984
页数:13
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