Matrix metalloproteinase-2 facilitates wound healing events that promote functional recovery after spinal cord injury
Matrix metalloproteinase-2 facilitates wound healing events that promote functional recovery after spinal cord injury
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DOI：
10.1523/jneurosci.1993-06.2006
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发表时间：
2006-09-27
影响因子：
5.3
通讯作者：
Noble-Haeusslein, Linda J.
中科院分区：
文献类型：
--
作者：
Hsu, Jung-Yu C.;McKeon, Robert;Noble-Haeusslein, Linda J.
基质金属蛋白酶（MMPs）是一种参与中枢神经系统损伤和修复机制的蛋白水解酶。仅在脊髓损伤后的头几天对MMPs进行药物阻断，可改善运动恢复。然而，当治疗扩展到急性损伤的脊髓以外，包括伤口愈合和组织重塑时，这种有益的反应就会消失。这表明一些MMPs在伤口愈合中起有益作用。为了验证这一假设，我们研究了MMP-2的作用，它在伤口愈合过程中积极表达，在脊髓损伤后白质保留和轴突可塑性，胶质疤痕的形成和运动恢复中。MMP-2在损伤后7 - 14天增加，免疫定位于病灶中心附近的反应性星形胶质细胞。在损伤的MMP-2缺失的动物中，白质保留减少，血清素能纤维减少。MMP-2缺乏也导致对硫酸软骨素蛋白聚糖的免疫反应性增加和更广泛的星形细胞疤痕。最重要的是，MMP-2缺失小鼠在开阔场地的运动、在旋转棒上的表现和网格行走明显受损。我们的研究结果表明，MMP-2通过调节神经胶质瘢痕的形成、白质保留和/或轴突可塑性来促进损伤后的功能恢复。因此，利用MMPs作为治疗靶点的策略必须平衡伤口愈合过程中的这些有益作用及其在急性损伤脊髓中的不良相互作用。
Matrix metalloproteinases (MMPs) are proteolytic enzymes that are involved in both injury and repair mechanisms in the CNS. Pharmacological blockade of MMPs, limited to the first several days after spinal cord injury, improves locomotor recovery. This beneficial response is, however, lost when treatment is extended beyond the acutely injured cord to include wound healing and tissue remodeling. This suggests that some MMPs play a beneficial role in wound healing. To test this hypothesis, we investigated the role of MMP-2, which is actively expressed during wound healing, in white matter sparing and axonal plasticity, the formation of a glial scar, and locomotor recovery after spinal cord injury. MMP-2 increased between 7 and 14 d after injury, where it was immunolocalized in reactive astrocytes bordering the lesion epicenter. There was reduced white matter sparing and fewer serotonergic fibers, caudal to the lesion in injured MMP-2 null animals. MMP-2 deficiency also resulted in increased immunoreactivity to chondroitin sulfate proteoglycans and a more extensive astrocytic scar. Most importantly, locomotion in an open field, performance on a rotarod, and grid walking were significantly impaired in injured MMP-2 null mice. Our findings suggest that MMP-2 promotes functional recovery after injury by regulating the formation of a glial scar and white matter sparing and/or axonal plasticity. Thus, strategies exploiting MMPs as therapeutic targets must balance these beneficial effects during wound healing with their adverse interactions in the acutely injured spinal cord.