Oncostatin M-induced astrocytic tissue inhibitor of metalloproteinases-1 drives remyelination

Evelien Houben; Kris Janssens; Doryssa Hermans; Jennifer Vandooren; Chris Van den Haute; Melissa Schepers; Tim Vanmierlo; Ivo Lambrichts; Jack van Horssen; Veerle Baekelandt; Ghislain Opdenakker; Wia Baron; Bieke Broux; Helena Slaets; Niels Hellings

doi:10.1073/pnas.1912910117

Oncostatin M-induced astrocytic tissue inhibitor of metalloproteinases-1 drives remyelination

Evelien Houben, Kris Janssens, Doryssa Hermans, Jennifer Vandooren, Chris Van den Haute, Melissa Schepers, Tim Vanmierlo, Ivo Lambrichts, Jack van Horssen, Veerle Baekelandt, Ghislain Opdenakker, Wia Baron, Bieke Broux, Helena Slaets, Niels Hellings^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

The brain's endogenous capacity to restore damaged myelin deteriorates during the course of demyelinating disorders. Currently, no treatment options are available to establish remyelination. Chronic demyelination leads to damaged axons and irreversible destruction of the central nervous system (CNS). We identified two promising therapeutic candidates which enhance remyelination: oncostatin M (OSM), a member of the interleukin-6 family, and downstream mediator tissue inhibitor of metalloproteinases-1 (TIMP-1). While remyelination was completely abrogated in OSMR beta knockout (KO) mice, OSM overexpression in the chronically demyelinated CNS established remyelination. Astrocytic TIMP-1 was demonstrated to play a pivotal role in OSM-mediated remyelination. Astrocyte-derived TIMP-1 drove differentiation of oligodendrocyte precursor cells into mature oligodendrocytes in vitro. In vivo, TIMP-1 deficiency completely abolished spontaneous remyelination, phenocopying OSMR beta KO mice. Finally, TIMP-1 was expressed by human astrocytes in demyelinated multiple sclerosis lesions, confirming the human value of our findings. Taken together, OSM and its downstream mediator TIMP-1 have the therapeutic potential to boost remyelination in demyelinating disorders.

Original language	English
Pages (from-to)	5028-5038
Number of pages	11
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	117
Issue number	9
DOIs	https://doi.org/10.1073/pnas.1912910117
Publication status	Published - 3 Mar 2020

Keywords

oncostatin M
remyelination
oligodendrocyte precursor cells
astrocytes
tissue inhibitor of metalloproteinases-1
OLIGODENDROCYTE PROGENITOR CELLS
CENTRAL-NERVOUS-SYSTEM
MULTIPLE-SCLEROSIS
MEDIATED DEMYELINATION
UP-REGULATION
RECEPTOR
EXPRESSION
CNS
PROTECTS
LIF

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060743Licence: Other

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Houben, E., Janssens, K., Hermans, D., Vandooren, J., Van den Haute, C., Schepers, M., Vanmierlo, T., Lambrichts, I., van Horssen, J., Baekelandt, V., Opdenakker, G., Baron, W., Broux, B., Slaets, H., & Hellings, N. (2020). Oncostatin M-induced astrocytic tissue inhibitor of metalloproteinases-1 drives remyelination. Proceedings of the National Academy of Sciences of the United States of America, 117(9), 5028-5038. https://doi.org/10.1073/pnas.1912910117

@article{eda9e24454104e00aced5f67d4c2100b,

title = "Oncostatin M-induced astrocytic tissue inhibitor of metalloproteinases-1 drives remyelination",

abstract = "The brain's endogenous capacity to restore damaged myelin deteriorates during the course of demyelinating disorders. Currently, no treatment options are available to establish remyelination. Chronic demyelination leads to damaged axons and irreversible destruction of the central nervous system (CNS). We identified two promising therapeutic candidates which enhance remyelination: oncostatin M (OSM), a member of the interleukin-6 family, and downstream mediator tissue inhibitor of metalloproteinases-1 (TIMP-1). While remyelination was completely abrogated in OSMR beta knockout (KO) mice, OSM overexpression in the chronically demyelinated CNS established remyelination. Astrocytic TIMP-1 was demonstrated to play a pivotal role in OSM-mediated remyelination. Astrocyte-derived TIMP-1 drove differentiation of oligodendrocyte precursor cells into mature oligodendrocytes in vitro. In vivo, TIMP-1 deficiency completely abolished spontaneous remyelination, phenocopying OSMR beta KO mice. Finally, TIMP-1 was expressed by human astrocytes in demyelinated multiple sclerosis lesions, confirming the human value of our findings. Taken together, OSM and its downstream mediator TIMP-1 have the therapeutic potential to boost remyelination in demyelinating disorders.",

keywords = "oncostatin M, remyelination, oligodendrocyte precursor cells, astrocytes, tissue inhibitor of metalloproteinases-1, OLIGODENDROCYTE PROGENITOR CELLS, CENTRAL-NERVOUS-SYSTEM, MULTIPLE-SCLEROSIS, MEDIATED DEMYELINATION, UP-REGULATION, RECEPTOR, EXPRESSION, CNS, PROTECTS, LIF",

author = "Evelien Houben and Kris Janssens and Doryssa Hermans and Jennifer Vandooren and {Van den Haute}, Chris and Melissa Schepers and Tim Vanmierlo and Ivo Lambrichts and {van Horssen}, Jack and Veerle Baekelandt and Ghislain Opdenakker and Wia Baron and Bieke Broux and Helena Slaets and Niels Hellings",

note = "Funding Information: ACKNOWLEDGMENTS. We thank Dr. Tom Struys, Katrien Wauterickx, and Joke Vanhoof for excellent technical assistance. This work was financially supported by grants from the Research Foundation of Flanders (FWO Vlaanderen, G04441N, G050617N, G0A5716N, and 1106817N), the Interuniversity Attraction Poles (IUAP-P7-39), the Belgian MS-Liga and the Charcot Foundation of Belgium, Methusalem NEURONET, the European FP7 project, HEALTH-F2-2011-278850 (INMiND), and Bijzonder Onderzoeksfonds (BOF)-UHasselt. Funding Information: We thank Dr. Tom Struys, Katrien Wauterickx, and Joke Vanhoof for excellent technical assistance. This work was financially supported by grants from the Research Foundation of Flanders (FWO Vlaanderen, G04441N, G050617N, G0A5716N, and 1106817N), the Interuniversity Attraction Poles (IUAP-P7-39), the Belgian MS-Liga and the Charcot Foundation of Belgium, Methusalem NEURONET, the European FP7 project, HEALTH-F2-2011-278850 (INMiND), and Bijzonder Onderzoeksfonds (BOF)UHasselt. Publisher Copyright: {\textcopyright} 2020 National Academy of Sciences. All rights reserved.",

year = "2020",

month = mar,

day = "3",

doi = "10.1073/pnas.1912910117",

language = "English",

volume = "117",

pages = "5028--5038",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "9",

}

Houben, E, Janssens, K, Hermans, D, Vandooren, J, Van den Haute, C, Schepers, M , Vanmierlo, T, Lambrichts, I, van Horssen, J, Baekelandt, V, Opdenakker, G, Baron, W, Broux, B, Slaets, H & Hellings, N 2020, 'Oncostatin M-induced astrocytic tissue inhibitor of metalloproteinases-1 drives remyelination', Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 9, pp. 5028-5038. https://doi.org/10.1073/pnas.1912910117

TY - JOUR

T1 - Oncostatin M-induced astrocytic tissue inhibitor of metalloproteinases-1 drives remyelination

AU - Houben, Evelien

AU - Janssens, Kris

AU - Hermans, Doryssa

AU - Vandooren, Jennifer

AU - Van den Haute, Chris

AU - Schepers, Melissa

AU - Vanmierlo, Tim

AU - Lambrichts, Ivo

AU - van Horssen, Jack

AU - Baekelandt, Veerle

AU - Opdenakker, Ghislain

AU - Baron, Wia

AU - Broux, Bieke

AU - Slaets, Helena

AU - Hellings, Niels

N1 - Funding Information: ACKNOWLEDGMENTS. We thank Dr. Tom Struys, Katrien Wauterickx, and Joke Vanhoof for excellent technical assistance. This work was financially supported by grants from the Research Foundation of Flanders (FWO Vlaanderen, G04441N, G050617N, G0A5716N, and 1106817N), the Interuniversity Attraction Poles (IUAP-P7-39), the Belgian MS-Liga and the Charcot Foundation of Belgium, Methusalem NEURONET, the European FP7 project, HEALTH-F2-2011-278850 (INMiND), and Bijzonder Onderzoeksfonds (BOF)-UHasselt. Funding Information: We thank Dr. Tom Struys, Katrien Wauterickx, and Joke Vanhoof for excellent technical assistance. This work was financially supported by grants from the Research Foundation of Flanders (FWO Vlaanderen, G04441N, G050617N, G0A5716N, and 1106817N), the Interuniversity Attraction Poles (IUAP-P7-39), the Belgian MS-Liga and the Charcot Foundation of Belgium, Methusalem NEURONET, the European FP7 project, HEALTH-F2-2011-278850 (INMiND), and Bijzonder Onderzoeksfonds (BOF)UHasselt. Publisher Copyright: © 2020 National Academy of Sciences. All rights reserved.

PY - 2020/3/3

Y1 - 2020/3/3

N2 - The brain's endogenous capacity to restore damaged myelin deteriorates during the course of demyelinating disorders. Currently, no treatment options are available to establish remyelination. Chronic demyelination leads to damaged axons and irreversible destruction of the central nervous system (CNS). We identified two promising therapeutic candidates which enhance remyelination: oncostatin M (OSM), a member of the interleukin-6 family, and downstream mediator tissue inhibitor of metalloproteinases-1 (TIMP-1). While remyelination was completely abrogated in OSMR beta knockout (KO) mice, OSM overexpression in the chronically demyelinated CNS established remyelination. Astrocytic TIMP-1 was demonstrated to play a pivotal role in OSM-mediated remyelination. Astrocyte-derived TIMP-1 drove differentiation of oligodendrocyte precursor cells into mature oligodendrocytes in vitro. In vivo, TIMP-1 deficiency completely abolished spontaneous remyelination, phenocopying OSMR beta KO mice. Finally, TIMP-1 was expressed by human astrocytes in demyelinated multiple sclerosis lesions, confirming the human value of our findings. Taken together, OSM and its downstream mediator TIMP-1 have the therapeutic potential to boost remyelination in demyelinating disorders.

AB - The brain's endogenous capacity to restore damaged myelin deteriorates during the course of demyelinating disorders. Currently, no treatment options are available to establish remyelination. Chronic demyelination leads to damaged axons and irreversible destruction of the central nervous system (CNS). We identified two promising therapeutic candidates which enhance remyelination: oncostatin M (OSM), a member of the interleukin-6 family, and downstream mediator tissue inhibitor of metalloproteinases-1 (TIMP-1). While remyelination was completely abrogated in OSMR beta knockout (KO) mice, OSM overexpression in the chronically demyelinated CNS established remyelination. Astrocytic TIMP-1 was demonstrated to play a pivotal role in OSM-mediated remyelination. Astrocyte-derived TIMP-1 drove differentiation of oligodendrocyte precursor cells into mature oligodendrocytes in vitro. In vivo, TIMP-1 deficiency completely abolished spontaneous remyelination, phenocopying OSMR beta KO mice. Finally, TIMP-1 was expressed by human astrocytes in demyelinated multiple sclerosis lesions, confirming the human value of our findings. Taken together, OSM and its downstream mediator TIMP-1 have the therapeutic potential to boost remyelination in demyelinating disorders.

KW - oncostatin M

KW - remyelination

KW - oligodendrocyte precursor cells

KW - astrocytes

KW - tissue inhibitor of metalloproteinases-1

KW - OLIGODENDROCYTE PROGENITOR CELLS

KW - CENTRAL-NERVOUS-SYSTEM

KW - MULTIPLE-SCLEROSIS

KW - MEDIATED DEMYELINATION

KW - UP-REGULATION

KW - RECEPTOR

KW - EXPRESSION

KW - CNS

KW - PROTECTS

KW - LIF

U2 - 10.1073/pnas.1912910117

DO - 10.1073/pnas.1912910117

M3 - Article

C2 - 32071226

SN - 0027-8424

VL - 117

SP - 5028

EP - 5038

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 9

ER -

Oncostatin M-induced astrocytic tissue inhibitor of metalloproteinases-1 drives remyelination

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Keywords

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