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J. Biol. Chem., Vol. 283, Issue 14, 9465-9474, April 4, 2008

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Collagenase-2 Deficiency or Inhibition Impairs Experimental Autoimmune Encephalomyelitis in Mice^*

Alicia R. Folgueras, Antonio Fueyo, Olivia García-Suárez^¶, Jennifer Cox^||, Aurora Astudillo^¶, Paolo Tortorella^**, Cristina Campestre, Ana Gutiérrez-Fernández, Miriam Fanjul-Fernández, Caroline J. Pennington, Dylan R. Edwards, Christopher M. Overall^||, and Carlos López-Otín¹

From the Departamento de Bioquímica y Biología Molecular, and Biología Funcional, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, and ^¶Servicio de Anatomía Patológica, Hospital Central de Asturias, Oviedo 33006, Spain, the ^||Departments of Oral Biological and Medical Sciences, and Biochemistry and Molecular Biology, Centre for Blood Research, University of British Columbia, Vancouver, V6T 1Z3 Canada, the ^**Dipartimento Farmaco-Chimico, Università degli Studi di Bari, Bari 70125, Italy, the Dipartimento di Scienze del Farmaco, Università G. d'Annunzio, Chieti 66013, Italy, and the School of Biological Sciences, University of East Anglia, Norwich, NR4 7TJ United Kingdom

Matrix metalloproteinases (MMPs) have been implicated in a variety of human diseases, including neuroimmunological disorders such as multiple sclerosis. However, the recent finding that some MMPs play paradoxical protective roles in these diseases has made necessary the detailed study of the specific function of each family member in their pathogenesis. To determine the relevance of collagenase-2 (MMP-8) in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, we have performed two different analyses involving genetic and biochemical approaches. First, we have analyzed the development of EAE in mutant mouse deficient in MMP-8, with the finding that the absence of this proteolytic enzyme is associated with a marked reduction in the clinical symptoms of EAE. We have also found that MMP-8^-/- mice exhibit a marked reduction in central nervous system-infiltrating cells and demyelinating lesions. As a second approach, we have carried out a pharmacological inhibition of MMP-8 with a selective inhibitor against this protease (IC₅₀ = 0.4 nM). These studies have revealed that the administration of the MMP-8 selective inhibitor to mice with EAE also reduces the severity of the disease. Based on these findings, we conclude that MMP-8 plays an important role in EAE development and propose that this enzyme may be a novel therapeutic target in human neuro-inflammatory diseases such as multiple sclerosis.

Received for publication, November 20, 2007 , and in revised form, January 28, 2008.

^* This work was supported by grants from Ministerio de Educación y Ciencia-Spain, Fundación M. Botín, Fundación Lilly, and European Union (Cancer Degradome-FP6). The Instituto Universitario de Oncología is supported by Obra Social Cajastur-Asturias. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 34-985-104-201; Fax: 34-985-103-564; E-mail: clo{at}uniovi.es.

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