Presence of Enzyme May Worsen Effects of Spinal Cord Injury and Impair Long-term Recovery

Findings suggest MMP-3 disruptsblood-spinal cord barrier and promotes hemorrhage, according to study publishedin The American Journal of Pathology

Philadelphia, PA, October 16, 2014

Traumatic spinal cord injury (SCI) is a devastatingcondition with few treatment options. Studies show that damage to the barrierseparating blood from the spinal cord can contribute to the neurologic deficitsthat arise secondary to the initial trauma. Through a series of sophisticatedexperiments, researchers reporting in The American Journal of Pathologysuggest that matrix metalloproteinase-3 (MMP-3) plays a pivotal role indisruption of the brain/spinal cord barrier (BSCB), cell death, and functionaldeficits after SCI. This link also presents new therapeutic possibilities.

"Matrix metalloproteinases (MMPs) are enzymes known todegrade the extracellular matrix and other extracellular proteins and areessential for remodeling of the extracellular matrix and wound healing.Excessive proteolytic activity of MMPs can be detrimental, leading to numerouspathological conditions, including blood brain barrier (BBB)/BSCB disruptionafter injury," explains Tae Young Yune, PhD, of the Department of Biochemistryand Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Korea.Although other MMPs have been linked to SCI (i.e. MMP-2, MMP-9, and MMP-12),there has been no previous direct evidence of a similar role for MMP-3.

By comparing mice that underwent spinal cord injury to acontrol group, investigators found that both MMP3 messenger RNA (mRNA) andMMP-3 protein levels in spinal cord segments were increased after SCI, peakingone day after surgery in the experimental group, whereas no changes were seenin the controls. MMP-3 immunoreactivity was detected in cells within the lesionsite, invading neutrophils, and blood vessel endothelial cells in the areaoutside of the initial injured area (the penumbra).

Another series of experiments focused on the role ofMMP-3 in BSCB permeability, using dye to visualize leakage through the BSCB.Similar to MMP-3 mRNA and protein levels, dye leakage reached a maximum one dayafter SCI. Leakage was lower in Mmp3 knockout mice that were geneticallyaltered to be deficient in MMP-3 as well as in mice injected with either Mmp3small interfering RNA (siRNA) or a general MMP inhibitor. Injection of MMP-3into normal spinal cord also significantly increased dye leakage.

MMP-3 was found to contribute to the degradation of tightjunction proteins that are responsible for maintaining the integrity of theBSCB barrier. In addition, the researchers reported that MMP-3 induced bloodcell infiltration and hemorrhage after SCI in wild-type mice, but not in Mmp3knockout mice.  MMP-3 also mediated activation of other MMPs (MMP-2 andMMP-9) that are up-regulated after SCI. "This is the first study to demonstratethat MMP-3 is involved in MMP-9 activation in central nervous system injury,"says Dr. Yune.

A significant finding was that mice deficient in MMP-3showed significantly better functional recovery 14 and 28 days after injurythan non-deficient mice. Histological analysis showed that after SCI the micedeficient in MMP-3 had smaller volumes of injured tissue and more healthy axonsthan non-deficient wild-type mice.

"The evidence suggests that BBB/BSCB disruption plays apivotal role in acute and chronic neurological disorders. The inhibition ofMMP-3 may be a promising therapeutic target for human central nervous systemdisease, including SCI," notes Dr. Yune.

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Notes for editors
"Matrixmetalloproteinase-3 promotes early blood-spinal cord barrier disruption andhemorrhage and impairs long-term neurological recovery after spinal cord injury,"by Jee Youn Lee, Hae Young Choi,Hyun-Jong Ahn, Bong Gun Ju, and Tae Young Yune. (DOI: http://dx.doi.org/10.1016/j.ajpath.2014.07.016). The article appears online ahead of The American Journal of Pathology, Volume 184/Issue 11 (November 2014) publishedby Elsevier.

This work was supported by the Pioneer Research CenterProgram through the National Research Foundation of Korea, funded by theMinistry of Science, Information and Communications Technology and FuturePlanning grant 2010-0019349 and a Korea Health Technology R&D Project grantthrough the Korea Health Industry Development Institute, funded by the Ministryof Health and Welfare, Republic of Korea, grant HI13C14600000.

Full text of the articles is available to credentialedjournalists upon request; contact Eileen Leahy at +1 732 238 3628 or ajpmedia@elsevier.com. Journalistswishing to interview the authors may contact Tae Young Yune, PhD, at +82 02 961 0968; +82 02 969 6343 (fax) or tyune@khu.ac.kr.

About The American Journal of Pathology
 The American Journal of Pathology (http://ajp.amjpathol.org), official journalof the American Society for Investigative Pathology, seeks to publishhigh-quality, original papers on the cellular and molecular biology of disease.The editors accept manuscripts that advance basic and translational knowledgeof the pathogenesis, classification, diagnosis, and mechanisms of disease,without preference for a specific analytic method. High priority is given tostudies on human disease and relevant experimental models using cellular,molecular, animal, biological, chemical, and immunological approaches inconjunction with morphology.

Theleading global forum for reporting quality original research on cellular andmolecular mechanisms of disease, TheAmerican Journal of Pathology isthe most highly cited journal in Pathology – over 39,000 cites in 2013 – withan Impact Factor of 4.602 and Eigenfactor of 0.07076 according to the 2013Journal Citation Reports®, Thomson Reuters, and an h-index of206 according to the 2013 SCImago Journal and Country Rank.

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