Publication

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

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., 3-Mar-2020, In : Proceedings of the National Academy of Sciences of the United States of America. 117, 9, p. 5028-5038 11 p.

Research output: Contribution to journalArticleAcademicpeer-review

Copy link to clipboard

Documents

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

    Final publisher's version, 3.09 MB, PDF document

    Request copy

DOI

  • 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

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 OSMRβ 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 OSMRβ 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 languageEnglish
Pages (from-to)5028-5038
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number9
Early online date18-Feb-2020
Publication statusPublished - 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

ID: 118430536