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
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 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.
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 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.
KW - Astrocytes
KW - Oligodendrocyte precursor cells
KW - Oncostatin M
KW - Remyelination
KW - Tissue inhibitor of metalloproteinases-1
UR - http://www.scopus.com/inward/record.url?scp=85081150705&partnerID=8YFLogxK
U2 - https://doi.org/10.1073/pnas.1912910117
DO - https://doi.org/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 -