I. LambrichtsBiomedical Research Institute - Hasselt University
Author Of 1 Presentation
PS14.04 - Oncostatin M-induced astrocytic tissue inhibitor of metalloproteinases-1 drives remyelination
The brain’s endogenous capacity to restore damaged myelin deteriorates during the course of demyelinating disorders including multiple sclerosis (MS). Currently, none of the available treatment options for MS directly establishes remyelination. We have previously shown that cytokines of the IL-6 family are upregulated in post mortem MS lesions and have regenerative potential in animal models of MS.
Here we investigated how oncostatin M (OSM), a member of the IL-6 family of cytokines, contributes to the remyelination process using animal model systems and aimed at identifying the underlying mode of action related to that.
Loss and gain of function experiments were performed using either knock out (KO) strains or CNS directed stereotactic application of lentiviral vectors (LV) that overexpress the transgene. The acute and chronic cuprizone induced demyelination model was used as an in vivo to investigate de- and remyelination. Primary oligodendrocyte and astrocyte cultures were used for in vitro experiments. Genes and proteins were identified by qPCR and/or western blotting. Pathological analyses were based on immunohistochemistry and electron microscopy.
OSM and its downstream mediator tissue inhibitor of metalloproteinases-1 (TIMP-1) were identified as two promising therapeutic targets. While remyelination was completely abrogated in OSM receptor (OSMRβ) KO mice, LV mediated 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.