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The Journal of Neuroscience, September 27, 2006, 26(39):9841-9850; doi:10.1523/JNEUROSCI.1993-06.2006

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Development/Plasticity/Repair
Matrix Metalloproteinase-2 Facilitates Wound Healing Events That Promote Functional Recovery after Spinal Cord Injury

Jung-Yu C. Hsu,¹ Robert McKeon,³ Staci Goussev,¹ Zena Werb,² Jung-Uek Lee,¹ Alpa Trivedi,¹ and Linda J. Noble-Haeusslein¹

Departments of ¹Neurological Surgery and ²Anatomy, University of California, San Francisco, California 94143, and ³Department of Cell Biology, Emory University, Atlanta, Georgia 30322

Correspondence should be addressed to Dr. Jung-Yu C. Hsu, Department of Neurological Surgery, University of California, 521 Parnassus Avenue, Room C224, San Francisco, CA 94143-0520. Email: jung-yu.hsu{at}ucsf.edu

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.

Key words: glial fibrillary acidic protein; chondroitin sulfate proteoglycan; astrogliosis; contusion injury; gelatinase A; extracellular matrix

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Received May 10, 2006; revised Aug. 4, 2006; accepted Aug. 10, 2006.

Correspondence should be addressed to Dr. Jung-Yu C. Hsu, Department of Neurological Surgery, University of California, 521 Parnassus Avenue, Room C224, San Francisco, CA 94143-0520. Email: jung-yu.hsu{at}ucsf.edu

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