Using your Noggin to Think about sequential factors to promote Remyelination

Sabo et al. Investigation of Sequential Growth Factor Delivery during Cuprizone Challenge in Mice Aimed to Enhance Oligodendrogliogenesis and Myelin Repair. PLoS One. 2013 May 1;8(5):e63415.

Repair in multiple sclerosis involves remyelination, a process in which axons are provided with a new myelin sheath by new oligodendrocytes. Bone morphogenic proteins (BMPs) are a family of growth factors that have been shown to influence the response of oligodendrocyte progenitor cells (OPCs) in vivo during demyelination and remyelination in the adult brain. We have previously shown that BMP4 infusion increases numbers of OPCs during cuprizone-induced demyelination, while infusion of Noggin, an endogenenous antagonist of BMP4 increases numbers of mature oligodendrocytes and remyelinated axons following recovery. Additional studies have shown that insulin-like growth factor-1 (IGF-1) promotes the survival of OPCs during cuprizone-induced demyelination. Based on these data, we investigated whether myelin repair could be further enhanced by sequential infusion of these agents firstly, BMP4 to increase OPC numbers, followed by either Noggin or IGF-1 to increase the differentiation and survival of the newly generated OPCs. We identified that sequential delivery of BMP4 and IGF-1 during cuprizone challenge increased the number of mature oligodendrocytes and decreased astrocyte numbers following recovery compared with vehicle infused mice, but did not alter remyelination. However, sequential delivery of BMP4 and Noggin during cuprizone challenge did not alter numbers of oligodendrocytes or astrocytes in the corpus callosum compared with vehicle infused mice. Our results suggest that while single delivery of Noggin or IGF-1 increased the production of mature oligodendrocytes in vivo in the context of demyelination, only Noggin infusion promoted remyelination. Thus, sequential delivery of BMP4 and Noggin or IGF-1 does not further enhance myelin repair above what occurs with delivery of Noggin alone.


This study first used BMP4 to increase the number of myelinating cells and Noggin is another molecule which can do the same thing and can promote remyelination. Noggin inactivates members of the transforming growth factor-beta (TGF-beta) superfamily signalling proteins, such as bone morphogenetic protein-4 (BMP4). It was wondered if you could use the growth factors sequentially to improve oligodendrocyte numbers and promote remyelination, but it didn't really work that way. 

One of the problems with the cuprizone model is that the norm is that they naturally remyelinate and repair so all the treatments can do is speed up a natural purpose. If there was a model with persistent demyelination this combination approach may still have milage. If at first you don't succeed try, try again...

Labels: