MMP-28 as a regulator of myelination.
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.


CONCLUSIONS
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.
Werner
Sean R
SR
Biotechnology Discovery Research, Lilly Corporate Center, Indianapolis, IN 46225, USA. sean.werner@sbcglobal.net
Dotzlaf
Joseph E
JE
Smith
Rosamund C
RC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D002525:Cerebellar Cortex / Q000166:cytology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D053505:Matrix Metalloproteinases, Secreted / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000378:metabolism / Q000473:pathology; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism*; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism; D011247:Pregnancy; D011485:Protein Binding; D051381:Rats; D020318:Rats, Long-Evans; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology
D000911:Antibodies, Monoclonal; D018992:Myelin-Associated Glycoprotein; C424663:MMP28 protein, human; D053505:Matrix Metalloproteinases, Secreted
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