Department of Immunology, Biomedical Research Institute, Hasselt University, 3590 Diepenbeek, Belgium.
Department of Microbiology and Immunology, Laboratory of Immunobiology, Rega Institute, Katholieke Universiteit (KU) Leuven, 3000 Leuven, Belgium.
Proc Natl Acad Sci U S A. 2020 Mar 3;117(9):5028-5038. doi: 10.1073/pnas.1912910117. Epub 2020 Feb 18.
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.
在脱髓鞘疾病的发生发展过程中，大脑内源性的髓鞘修复能力逐渐下降。目前，尚无有效的治疗方法来建立髓鞘的再形成。慢性脱髓鞘导致轴突受损，中枢神经系统（CNS）不可逆转地破坏。我们鉴定出两种有前途的治疗候选物，可增强髓鞘的再形成：白细胞介素-6 家族成员之一的肿瘤坏死因子-α（OSM）和下游介质基质金属蛋白酶组织抑制剂-1（TIMP-1）。虽然 OSMRβ 敲除（KO）小鼠的髓鞘再形成完全被阻断，但在慢性脱髓鞘的中枢神经系统中过表达 OSM 可建立髓鞘再形成。星形胶质细胞 TIMP-1 被证明在 OSM 介导的髓鞘再形成中发挥关键作用。星形胶质细胞衍生的 TIMP-1 可驱动体外少突胶质前体细胞向成熟少突胶质细胞分化。在体内，TIMP-1 缺乏完全消除了自发的髓鞘再形成，与 OSMRβ KO 小鼠表型相同。最后，TIMP-1 在脱髓鞘多发性硬化症病变中的人类星形胶质细胞中表达，证实了我们研究结果的人类价值。综上所述，OSM 及其下游介质 TIMP-1 具有在脱髓鞘疾病中促进髓鞘再形成的治疗潜力。
