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The Journal of Neuroscience, December 10, 2008, 28(50):13467-13477; doi:10.1523/JNEUROSCI.2287-08.2008
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Development/Plasticity/Repair
Matrix Metalloproteinase-9 Facilitates Glial Scar Formation in the Injured Spinal Cord
Jung-Yu C. Hsu,1,5 Lilly Y. W. Bourguignon,2 Christen M. Adams,1 Karine Peyrollier,2 Haoqian Zhang,1 Thomas Fandel,1 Christine L. Cun,1 Zena Werb,3 andLinda J. Noble-Haeusslein1,4 1Department of Neurological Surgery, 2Department of Medicine and Veterans Affair Medical Center, and Departments of 3Anatomy and 4Physical Therapy and Rehabilitation Science, University of California, San Francisco, California 94143, and 5Department of Cell Biology and Anatomy, National Cheng Kung University College of Medicine, Tainan 70101, Taiwan
Correspondence should be addressed to Dr. Jung-Yu C. Hsu, Department of Cell Biology and Anatomy, National Cheng Kung University College of Medicine, 1 University Road, Tainan 70101, Taiwan. Email: jungyu.hsu{at}gmail.com
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.
Key words: gelatinase; glial fibrillary acidic protein; chondroitin sulfate proteoglycan; extracellular matrix; actin; Rac1
Received May 19, 2008; revised Oct. 26, 2008; accepted Oct. 31, 2008.
Correspondence should be addressed to Dr. Jung-Yu C. Hsu, Department of Cell Biology and Anatomy, National Cheng Kung University College of Medicine, 1 University Road, Tainan 70101, Taiwan. Email: jungyu.hsu{at}gmail.com
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[Abstract] [Full Text] [PDF]
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