MMP-28 as a regulator of myelination

Sean R Werner,Rosamund C Smith,Joseph E Dotzlaf

doi:10.1186/1471-2202-9-83

Sean R Werner, Rosamund C Smith + Show 1 more

Open Access

https://doi.org/10.1186/1471-2202-9-83

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Journal: BMC neuroscience	Publication Date: Sep 9, 2008
Citations: 38	License type: CC BY 2.0

Affiliation: Eli Lilly (United States)

Abstract

BackgroundMatrix 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.ResultsMMP-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.ConclusionMMP-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.

Highlights

Matrix metalloproteinase-28 (MMP-28) is a poorly understood member of the matrix metalloproteinase family
MMP-28 was included in the media at concentrations of 0, 10 or 20 nM on day 0 and day three following the induction of myelination
Alteration of signaling pathways after MMP-28 inhibition To begin to understand the mechanism responsible for increased myelination seen in dorsal root ganglion (DRG) cultures with antiMMP-28 antibodies, we evaluated the ability of MMP-28 to alter signaling pathways that are known to be important in the development of myelin

Summary

Introduction

Matrix metalloproteinase-28 (MMP-28) is a poorly understood member of the matrix metalloproteinase family. Axonal Neuregulin-1 (Nrg-1) signaling stimulates either glial proliferation [9] or induces the differentiation of nonmyelinating Schwann cells and oligodendrocytes resulting in myelination depending on localization and amount of Nrg-1 [8]. The explanation of these opposing activities may relate to the downstream signaling pathways activated by Nrg-1. The details of the intracellular signaling controlling this balance between proliferation and differentiation are still being elucidated but have been suggested to involve Nrg isoform expression, type I, II, or III [8,12] and proteolysis [8,13,14]. Nrg-1 type III contains a membrane bound (page number not for citation purposes)

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