Collagenase-2 deficiency or inhibition impairs experimental autoimmune encephalomyelitis in mice.
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 (IC(50) = 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.
Folgueras
Alicia R
AR
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.
Fueyo
Antonio
A
García-Suárez
Olivia
O
Cox
Jennifer
J
Astudillo
Aurora
A
Tortorella
Paolo
P
Campestre
Cristina
C
Gutiérrez-Fernández
Ana
A
Fanjul-Fernández
Miriam
M
Pennington
Caroline J
CJ
Edwards
Dylan R
DR
Overall
Christopher M
CM
López-Otín
Carlos
C
D000818:Animals; D002490:Central Nervous System / Q000201:enzymology* / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D020784:Matrix Metalloproteinase 8 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use
D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D020784:Matrix Metalloproteinase 8