Multiple sclerosis (MS) is a disease of the central nervous system with autoimmune etiology. Susceptibility to MS is linked to viral and
bacterial infections.
Matrix metalloproteinases (
MMPs) play a significant role in the fragmentation of
myelin basic protein (MBP) and
demyelination. The splice variants of the single MBP gene are expressed in the oligodendrocytes of the central nervous system (classic MBP) and in the immune cells (Golli-MBPs). Our data suggest that persistent
inflammation caused by environmental risk factors is a step to MS. We have discovered biochemical evidence suggesting the presence of the inflammatory proteolytic pathway leading to MS. The pathway involves the self-activated
furin and PC2
proprotein convertases and membrane type-6
MMP (MT6-
MMP/
MMP-25) that is activated by
furin/PC2. These events are followed by
MMP-25 proteolysis of the Golli-MBP
isoforms in the immune system cells and stimulation of the specific autoimmune T cell clones. It is likely that the passage of these autoimmune T cell clones through the disrupted blood-brain barrier to the brain and the recognition of neuronal, classic MBP causes
inflammation leading to the further up-regulation of the activity of the multiple individual
MMPs, the massive cleavage of MBP in the brain,
demyelination, and MS. In addition to the cleavage of Golli-MBPs,
MMP-25 proteolysis readily inactivates
crystallin alphaB that is a suppressor of MS. These data suggest that
MMP-25 plays an important role in MS pathology and that
MMP-25, especially because of its restricted cell/tissue expression pattern and cell surface/
lipid raft localization, is a promising drug target in MS.