The aim of this project was to
determine the role of the Tissue Inhibitor of Matrix
Metalloproteinases 3 (TIMP-3) in experimental allergic
encephalomyelitis (EAE); a model for the human disease
multiple sclerosis (MS). TIMP-3 is a potent inhibitor of
matrix metalloproteases and regulates angiogenesis as well as
apoptosis. During the acute phase of EAE, the clinical course
in either the actively or passively induced disease was
comparable to the TIMP-3-deficient (TIMP-3-/-) and wildtype
(WT) mice. However, during the late phase of the disease,
remission was significantly less pronounced in TIMP-3-/- mice
compared with WT mice (*p≤0.05). The histopathological
examinations of the spinal cords revealed that demyelinated
lesions persisted and were more prominent in TIMP-3-/- mice
than in WT mice. In parallel, the spinal cord of TIMP-3-/-
mice showed a reduced density of proliferating
oligodendroglial precursor cells which are critical for
re-myelination. In addition, in the spinal cord of TIMP-3-/-
mice the expression of pro-apoptotic ADAM-17 and caspase-3
was increased at the mRNA level when compared with WT mice.
The ELISA analysis of TNF from the spinal cord revealed
higher levels of soluble TNF in TIMP-3-/- mice compared with
WT mice; this promotes through TNFR1(tumor necrosis factor
receptor 1) the apoptosis of the oligodendroglial
progenitors. In parallel, reduced levels of membrane-bound
TNF have been measured in TIMP-3-/- mice; this promotes
through TNFR2 (tumor necrosis factor receptor 2) the
accumulation of proliferating oligodendrocyte progenitors.
These results demonstrate that TIMP-3 is important for
re-myelination in the spinal cord during EAE. Absence of
remission from EAE in TIMP-3-/- mice is accompanied by a
shift in TNF activation which could contribute to defective
re-myelination through influencing the density of
oligodendroglial precursor cells. This work contributes to
our understanding of re-myelination and might lead to new
therapeutic approaches for the patients with MS.