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Metalloproteinases have been implicated in the pathogenesis of multiple sclerosis. We report longitudinal serum levels of gelatinase B and of the tissue inhibitors of matrix metalloproteinases (TIMP), TIMP-1 and TIMP-2, in 21 patients with relapsing multiple sclerosis. Patients had monthly clinical and gadolinium-enhanced MRI follow-up for 10 months. Longitudinal samples in nine healthy controls and cross-sectional samples from 12 patients with inflammatory CNS disease and 15 patients with other neurological diseases were used for comparison. Average serum gelatinase B, TIMP-1 and TIMP-2 levels were significantly higher in multiple sclerosis patients and those with other neurological diseases than in healthy controls. In the patients with multiple sclerosis, gelatinase B levels were significantly higher during clinical relapse compared with periods of clinical stability. Multiple sclerosis patients with high mean serum gelatinase B levels had significantly more T1-weighted gadolinium-enhancing MRI lesions than those with mean levels within the control range. TIMP-1 levels were not different during relapse and between relapses. There was a trend for TIMP-2 levels to be lower during relapse compared with non-relapse periods. For similar levels of serum gelatinase B, associated TIMP-1 levels were significantly lower and TIMP-2 levels significantly higher in multiple sclerosis patients compared with the inflammatory CNS control group. We propose that an abnormality in the inhibitory response to metalloproteinases may play an aetiological role in the chronicity of multiple sclerosis.

Matrix metalloproteinases (MMPs) are a family of endopeptidases capable of enzymatic digestion of subendothelial basement membrane and other components of the extracellular matrix. Expression of MMP-2, -3, -7 and -9 is increased around multiple sclerosis plaques and in brain tissue in experimental allergic encephalomyelitis. To measure quantitatively the expression of these MMPs and their endogenous inhibitors (TIMP-1 and -2), we analysed samples from 52 patients with relapsing-remitting and primary progressive multiple sclerosis by ELISA (enzyme-linked immunosorbent assay) and substrate-gel electrophoresis (zymography). MMP-9 was increased over controls in 100% of relapsing-remitting multiple sclerosis cases, with similar levels detected in relapses and clinically stable phases of disease. In primary progressive multiple sclerosis, MMP-9 was increased in 57% of CSF samples, but concentrations were below those encountered in the relapsing-remitting form. The selective upregulation of MMP-9 suggests that T-cells and macrophages invading the brain parenchyma and the CSF space are the predominant source of MMP-9 in multiple sclerosis. TIMPs and other MMPs (MMP-2 and -3) were not upregulated or not detectable (MMP-7) in CSF of patients with relapsing-remitting and primary progressive multiple sclerosis. The sustained increase of MMP-9 in clinically stable multiple sclerosis supports the concept that multiple sclerosis is associated with ongoing proteolysis that may result in progressive tissue damage. The selective inhibition of MMP-9 could be a useful approach for the prevention of disease progression in multiple sclerosis.