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MMP7 cleaves remyelination‐impairing fibronectin aggregates and its expression is reduced in chronic multiple sclerosis lesions

Upon demyelination, transient expression of fibronectin precedes successful remyelination. However, in chronic demyelination observed in multiple sclerosis (MS), aggregates of fibronectin persist and contribute to remyelination failure. Accordingly, removing fibronectin (aggregates) would constitute...

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Autores principales: Wang, Peng, Gorter, Rianne P., de Jonge, Jenny C., Nazmuddin, Muhammad, Zhao, Chao, Amor, Sandra, Hoekstra, Dick, Baron, Wia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099312/
https://www.ncbi.nlm.nih.gov/pubmed/29600597
http://dx.doi.org/10.1002/glia.23328
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author Wang, Peng
Gorter, Rianne P.
de Jonge, Jenny C.
Nazmuddin, Muhammad
Zhao, Chao
Amor, Sandra
Hoekstra, Dick
Baron, Wia
author_facet Wang, Peng
Gorter, Rianne P.
de Jonge, Jenny C.
Nazmuddin, Muhammad
Zhao, Chao
Amor, Sandra
Hoekstra, Dick
Baron, Wia
author_sort Wang, Peng
collection PubMed
description Upon demyelination, transient expression of fibronectin precedes successful remyelination. However, in chronic demyelination observed in multiple sclerosis (MS), aggregates of fibronectin persist and contribute to remyelination failure. Accordingly, removing fibronectin (aggregates) would constitute an effective strategy for promoting remyelination. Matrix metalloproteinases (MMPs) are enzymes known to remodel extracellular matrix components, including fibronectin. Here, we examined the ability of MMPs to degrade fibronectin aggregates. Our findings reveal that MMP7 cleaved fibronectin aggregates resulting into a prominent 13 kDa EIIIA (16 kDa EDA)‐containing fragment. MMP7 was upregulated during lysolecithin‐induced demyelination, indicating its potential for endogenous fibronectin clearance. In contrast, the expression of proMMP7 was substantially decreased in chronic active and inactive MS lesions compared with control white matter and remyelinated MS lesions. Microglia and macrophages were major cellular sources of proMMP7 and IL‐4‐activated, but not IFNγ+LPS‐activated, microglia and macrophages secreted significant levels of proMMP7. Also, conditioned medium of IL‐4‐activated macrophages most efficiently cleaved fibronectin aggregates upon MMP‐activating conditions. Yet, coatings of MMP7‐cleaved fibronectin aggregate fragments inhibited oligodendrocyte maturation, indicating that further degradation and/or clearance by phagocytosis is essential. These findings suggest that MMP7 cleaves fibronectin aggregates, while reduced (pro)MMP7 levels in MS lesions contribute to their persistent presence. Therefore, upregulating MMP7 levels may be key to remove remyelination‐impairing fibronectin aggregates in MS lesions.
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spelling pubmed-60993122018-08-23 MMP7 cleaves remyelination‐impairing fibronectin aggregates and its expression is reduced in chronic multiple sclerosis lesions Wang, Peng Gorter, Rianne P. de Jonge, Jenny C. Nazmuddin, Muhammad Zhao, Chao Amor, Sandra Hoekstra, Dick Baron, Wia Glia Research Articles Upon demyelination, transient expression of fibronectin precedes successful remyelination. However, in chronic demyelination observed in multiple sclerosis (MS), aggregates of fibronectin persist and contribute to remyelination failure. Accordingly, removing fibronectin (aggregates) would constitute an effective strategy for promoting remyelination. Matrix metalloproteinases (MMPs) are enzymes known to remodel extracellular matrix components, including fibronectin. Here, we examined the ability of MMPs to degrade fibronectin aggregates. Our findings reveal that MMP7 cleaved fibronectin aggregates resulting into a prominent 13 kDa EIIIA (16 kDa EDA)‐containing fragment. MMP7 was upregulated during lysolecithin‐induced demyelination, indicating its potential for endogenous fibronectin clearance. In contrast, the expression of proMMP7 was substantially decreased in chronic active and inactive MS lesions compared with control white matter and remyelinated MS lesions. Microglia and macrophages were major cellular sources of proMMP7 and IL‐4‐activated, but not IFNγ+LPS‐activated, microglia and macrophages secreted significant levels of proMMP7. Also, conditioned medium of IL‐4‐activated macrophages most efficiently cleaved fibronectin aggregates upon MMP‐activating conditions. Yet, coatings of MMP7‐cleaved fibronectin aggregate fragments inhibited oligodendrocyte maturation, indicating that further degradation and/or clearance by phagocytosis is essential. These findings suggest that MMP7 cleaves fibronectin aggregates, while reduced (pro)MMP7 levels in MS lesions contribute to their persistent presence. Therefore, upregulating MMP7 levels may be key to remove remyelination‐impairing fibronectin aggregates in MS lesions. John Wiley and Sons Inc. 2018-03-30 2018-08 /pmc/articles/PMC6099312/ /pubmed/29600597 http://dx.doi.org/10.1002/glia.23328 Text en © 2018 The Authors GLIA Published by Wiley Periodicals, Inc. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Wang, Peng
Gorter, Rianne P.
de Jonge, Jenny C.
Nazmuddin, Muhammad
Zhao, Chao
Amor, Sandra
Hoekstra, Dick
Baron, Wia
MMP7 cleaves remyelination‐impairing fibronectin aggregates and its expression is reduced in chronic multiple sclerosis lesions
title MMP7 cleaves remyelination‐impairing fibronectin aggregates and its expression is reduced in chronic multiple sclerosis lesions
title_full MMP7 cleaves remyelination‐impairing fibronectin aggregates and its expression is reduced in chronic multiple sclerosis lesions
title_fullStr MMP7 cleaves remyelination‐impairing fibronectin aggregates and its expression is reduced in chronic multiple sclerosis lesions
title_full_unstemmed MMP7 cleaves remyelination‐impairing fibronectin aggregates and its expression is reduced in chronic multiple sclerosis lesions
title_short MMP7 cleaves remyelination‐impairing fibronectin aggregates and its expression is reduced in chronic multiple sclerosis lesions
title_sort mmp7 cleaves remyelination‐impairing fibronectin aggregates and its expression is reduced in chronic multiple sclerosis lesions
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099312/
https://www.ncbi.nlm.nih.gov/pubmed/29600597
http://dx.doi.org/10.1002/glia.23328
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