Matrix Metalloproteinase-3 Promotes Early Blood-Spinal Cord Barrier Disruption and Hemorrhage and Impairs Long-Term Neurological Recovery after Spinal Cord Injury
Matrix Metalloproteinase-3 Promotes Early Blood-Spinal Cord Barrier Disruption and Hemorrhage and Impairs Long-Term Neurological Recovery after Spinal Cord Injury
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DOI：
10.1016/j.ajpath.2014.07.016
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发表时间：
2014-11-01
影响因子：
6
通讯作者：
Yune, Tae Young
中科院分区：
文献类型：
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作者：
Lee, Jee Youn;Choi, Hae Young;Yune, Tae Young
脊髓损伤(SCI)后，基质金属蛋白酶(MMPs)破坏血脊髓屏障(BSCB)，导致血脊髓屏障通透性增加，血细胞浸润，导致永久性神经功能障碍。在此，我们报道了基质金属蛋白酶-3在小鼠脊髓损伤后BSCB破坏中起关键作用。脊髓损伤后，中性粒细胞和血管中均有基质金属蛋白酶-3的表达，而转录因子核因子-kappaB参与了基质金属蛋白酶-3的表达。Mmp3基因敲除(KO)小鼠的BSCB通透性和血细胞渗透性较野生型(WT)小鼠明显降低，Mmp3 siRNA或MMPs的通用抑制剂N-异丁基-N-(4-甲氧基苯磺酰基)甘氨酰异羟肟酸可显著抑制KO小鼠的BSCB通透性和血细胞渗透。Mmp3KO组小鼠脊髓损伤后紧密连接蛋白如occludin和zonula occludens-1的表达水平也高于WT组。外源性，将基质金属蛋白酶-3注射到正常脊髓也可引起骨髓间充质干细胞通透性。此外，损伤后基质金属蛋白酶-9的活化是通过基质金属蛋白酶-3的活化来实现的。最后，与WT小鼠相比，Mmp3KO小鼠在损伤后的功能恢复方面有所改善。这些结果首次证实了MMP3在脊髓损伤后BSCB断裂中的作用，提示MMP3的调节可以作为抑制BSCB断裂和出血的治疗靶点，从而促进急性SCI后的功能恢复。
After spinal cord injury (SCI), blood-spinal cord barrier (BSCB) disruption by matrix metalloproteinases (MMPs) leads to BSCB permeability and blood cell infiltration, contributing to permanent neurological disability. Herein, we report that MMP-3 plays a critical role in BSCB disruption after SCI in mice. MMP-3 was induced in infiltrated neutrophils and blood vessels after SCI, and NF-kappa B as a transcription factor was involved in MMP-3 expression. BSCB permeability and blood cell infiltration after injury were more reduced in Mmp3 knockout (KO) mice than in wild-type (WT) mice, which was significantly inhibited by Mmp3 siRNA or a general inhibitor of MMPs, N-isobutyl-N-(4-methoxyphenylsulfonyl)glycyl hydroxamic acid. The Level of tight junction proteins, such as occludin and zonula occludens-1, which decreased after SCI, was also higher in Mmp3 KO than in WT mice. Exogenously, MMP-3 injection into the normal spinal cord also induced BSCB permeability. Furthermore, MMP-9 activation after injury was mediated by MMP-3 activation. Finally, improved functional recovery was observed in Mmp3 KO mice compared with WT mice after injury. These results demonstrated the role of MMP-3 in BSCB disruption after SCI for the first time and suggest that the regulation of MMP-3 can be considered a therapeutic target to inhibit BSCB disruption and hemorrhage, and thereby enhance functional recovery after acute SCI.