Cleavage of osteopontin by matrix metalloproteinase-12 modulates experimental autoimmune encephalomyelitis disease in C57BL/6 mice.

A role for osteopontin (OPN) in promoting disease activity of multiple sclerosis or its animal model experimental autoimmune encephalomyelitis (EAE) has recently been suggested. As the biological activity of OPN is heavily influenced by posttranslational processing, we investigated the capacity of matrix metalloproteinase (MMP)-12 to cleave OPN and determined whether this influenced disease activity. We found that OPN mRNA and protein expression in the spinal cord increased with EAE disease in C57BL/6 mice concurrently with MMP-12 expression. A Western blot of EAE and control spinal cords revealed different OPN-immunoreactive bands, with a pattern that was similar to MMP-12 cleavage of recombinant OPN in vitro. In addition, OPN fragments in the spinal cord of EAE-afflicted mice were reduced in MMP-12(-/-) mice compared with wild-type controls. However, examination of OPN(-/-) mice in short- and long-term experiments revealed no difference in EAE outcomes from wild-type animals. OPN/MMP-12 double null mice were generated, and it was revealed that MMP-12(-/-) mice had a worsening of disease compared with wild-type mice, which returned to wild-type levels in the OPN/MMP-12 double null mice. These results suggest that EAE disease activity may be modulated by the cleavage of OPN by MMP-12.

Matrix metalloproteinase-12 deficiency worsens relapsing-remitting experimental autoimmune encephalomyelitis in association with cytokine and chemokine dysregulation.

The elevation of several members of the matrix metalloproteinase (MMP) family promotes the pathophysiology of both multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Nonetheless, given the multiple activities of MMPs, it remains possible that increased levels of a particular MMP may have beneficial functions during disease progression. We reported previously that MMP-12(-/-) mice of the 129/SvEv strain had a poorer EAE outcome than wild-type controls. However, we did not determine further differences in disease profiles between these groups. Using the EAE model in 129/SvEv mice, we report that disease in both wild-type and MMP-12(-/-) mice follows a relapsing-remitting course. Although both mouse groups had similar clinical onsets, subsequent relapses were more severe in MMP-12(-/-) mice; their residual disability at remission was also higher compared with wild-type controls. The worsened relapses and remissions in MMP-12(-/-) mice occurred despite a deficiency of the antigen recall capacity of lymph node-derived cells as well as a reduction in the proportion of macrophages in the spinal cord during the chronic phase of EAE. Significantly, large increases of levels of chemokines and cytokines were found in the spinal cords of MMP-12(-/-) mice during chronic EAE. These results highlight MMP-12 as a beneficial enzyme in EAE and suggest that therapeutic interventions in multiple sclerosis should avoid targeting MMP-12.

Elevation of matrix metalloproteinases (MMPs) in multiple sclerosis and impact of immunomodulators.

The matrix metalloproteinases (MMPs) are implicated in the pathology of multiple sclerosis (MS). This review summarizes the consequences of upregulation of MMP members in MS as well as in an animal model of the disease, experimental autoimmune encephalomyelitis (EAE). The pathogenic roles of MMPs are considered, especially in the transmigration of leukocytes into the CNS. We review the evidence that interferon-beta, an immunomodulator that is commonly used in MS, affects MMP expression in the disease. The potential of minocycline as a therapy in MS, based on its activity as an MMP inhibitor, is discussed. Besides affecting MMPs, minocycline may have other actions that help account for its possible utility in MS.