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Open Access Highly Accessed Research article

MMP-28 as a regulator of myelination

Sean R Werner1*, Joseph E Dotzlaf2 and Rosamund C Smith1

Author affiliations

1 Biotechnology Discovery Research, Lilly Corporate Center, Indianapolis, IN, 46225, USA

2 Integrative Biology, Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, 46225, USA

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Citation and License

BMC Neuroscience 2008, 9:83  doi:10.1186/1471-2202-9-83

Published: 9 September 2008

Abstract

Background

Matrix metalloproteinase-28 (MMP-28) is a poorly understood member of the matrix metalloproteinase family. Metalloproteinases are important mediators in the development of the nervous system and can contribute to the maturation of the neural micro-environment.

Results

MMP-28 added to myelinating rat dorsal root ganglion (DRG) co-cultures reduces myelination and two antibodies targeted to MMP-28 (pAb180 and pAb183) are capable of binding MMP-28 and inhibiting its activity in a dose-dependent manner. Addition of 30 nM pAb180 or pAb183 to rat DRG cultures resulted in the 2.6 and 4.8 fold enhancement of myelination respectively while addition of MMP-28 to DRG co-cultures resulted in enhanced MAPK, ErbB2 and ErbB3 phosphorylation. MMP-28 protein expression was increased within demyelinated lesions of mouse experimental autoimmune encephalitis (EAE) and human multiple sclerosis lesions compared to surrounding normal tissue.

Conclusion

MMP-28 is upregulated in conditions of demyelination in vivo, induces signaling in vitro consistent with myelination inhibition and, neutralization of MMP-28 activity can enhance myelination in vitro. These results suggest inhibition of MMP-28 may be beneficial under conditions of dysmyelination.