Matrix metalloproteinase-9 facilitates glial scar formation in the injured spinal cord

Jung Yu C. Hsu, Lilly Y.W. Bourguignon, Christen M. Adams, Karine Peyrollier, Haoqian Zhang, Thomas Fandel, Christine L. Cun, Zena Werb, Linda J. Noble-Haeusslein

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Abstract

In the injured spinal cord, a glial scar forms and becomes a major obstacle to axonal regeneration. Formation of the glial scar involves migration of astrocytes toward the lesion. Matrix metalloproteinases (MMPs), including MMP-9 and MMP-2, govern cell migration through their ability to degrade constituents of the extracellular matrix. Although MMP-9 is expressed in reactive astrocytes, its involvement in astrocyte migration and formation of a glial scar is unknown. Here we found that spinal cord injured, wild-type mice expressing MMPs developed a more severe glial scar and enhanced expression of chondroitin sulfate proteoglycans, indicative of a more inhibitory environment for axonal regeneration/plasticity, than MMP-9 null mice. To determine whether MMP-9 mediates astrocyte migration, we conducted a scratch wound assay using astrocytes cultured from MMP-9 null, MMP-2 null, and wild-type mice. Gelatin zymography confirmed the expression of MMP-9 and MMP-2 in wild-type cultures. MMP-9 null astrocytes and wild-type astrocytes, treated with an MMP-9 inhibitor, exhibited impaired migration relative to untreated wild-type controls. MMP-9 null astrocytes showed abnormalities in the actin cytoskeletal organization and function but no detectable untoward effects on proliferation, cellular viability, or adhesion. Interestingly, MMP-2 null astrocytes showed increased migration, which could be attenuated in the presence of an MMP-9 inhibitor. Collectively, our studies provide explicit evidence that MMP-9 is integral to the formation of an inhibitory glial scar and cytoskeleton-mediated astrocyte migration. MMP-9 may thus be a promising therapeutic target to reduce glial scarring during wound healing after spinal cord injury.

Original languageEnglish
Pages (from-to)13467-13477
Number of pages11
JournalJournal of Neuroscience
Volume28
Issue number50
DOIs
Publication statusPublished - 2008 Dec 10

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

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    Hsu, J. Y. C., Bourguignon, L. Y. W., Adams, C. M., Peyrollier, K., Zhang, H., Fandel, T., Cun, C. L., Werb, Z., & Noble-Haeusslein, L. J. (2008). Matrix metalloproteinase-9 facilitates glial scar formation in the injured spinal cord. Journal of Neuroscience, 28(50), 13467-13477. https://doi.org/10.1523/JNEUROSCI.2287-08.2008