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The Journal of Neuroscience, November 5, 2003, 23(31):10107-10115

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Development/Plasticity/Repair
An Adverse Role for Matrix Metalloproteinase 12 after Spinal Cord Injury in Mice

Jennifer E. A. Wells,¹ Tiffany K. Rice,¹ Robert K. Nuttall,³ Dylan R. Edwards,³ Hakima Zekki,⁴ Serge Rivest,⁴ and V. Wee Yong^1,2

Departments of ¹Clinical Neurosciences and ²Oncology, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada, ³School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, United Kingdom, and ⁴Laboratory of Molecular Endocrinology and Department of Anatomy and Physiology, Laval University, Quebec, Quebec G1V 4G2, Canada

We investigated the role of matrix metalloproteinases (MMPs) in acute spinal cord injury (SCI). Transcripts encoding 22 of the 23 known mammalian MMPs were measured in the mouse spinal cord at various time points after injury. Although there were significant changes in the expression levels of multiple MMPs, MMP-12 was increased 189-fold over normal levels, the highest of all MMPs examined. To evaluate the role of MMP-12 in SCI, spinal cord compression was performed in wild-type (WT) and MMP-12 null mice. Behavioral analyses were conducted for 4 weeks using the Basso-Beattie-Bresnahan (BBB) locomotor rating scale as well as the inclined plane test. The results show that MMP-12 null mice exhibited significantly improved functional recovery compared with WT controls. Twenty-eight days after injury, the BBB score in the MMP-12 group was 7, representing extensive movement of all three hindlimb joints, compared with 4 in the WT group, representing only slight movement of these joints. Furthermore, MMP-12 null mice showed recovery of hindlimb strength more rapidly than control mice, with significantly higher inclined plane scores on days 14 and 21 after SCI. Mechanistically, there was decreased permeability of the blood-spinal barrier and reduced microglial and macrophage density in MMP-12 null mice compared with WT controls. This is the first study to profile the expression patterns of a majority of the known MMPs after spinal cord compression. The data indicate that MMP-12 expression after spinal cord trauma is deleterious and contributes to the development of secondary injury in SCI.

Key words: metalloproteinase; trauma; spinal cord injury; neuroinflammation; recovery; microglia

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Received July 15, 2003; revised August 21, 2003; accepted September 12, 2003.

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