Matrix metalloproteinase-9 (gelatinase B) is selectively elevated in CSF during relapses and stable phases of multiple sclerosis

Matrix metalloproteinases (MMPs) are a family of endopeptidases capable of enzymatic digestion of subendothelial basement membrane and other component s of the extracellular matrix. Expression of MMP-2, -3, -7 and -9 is increa sed around multiple sclerosis plaques and in brain tissue in experimental a llergic encephalomyelitis. To measure quantitatively the expression of thes e 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 e lectrophoresis (zymography). MMP-9 was increased over controls in 100% of r elapsing-remitting multiple sclerosis cases, with similar levels detected i n relapses and clinically stable phases of disease. In primary progressive multiple sclerosis, MMP-9 was increased in 57% of CSF samples, but concentr ations were below those encountered in the relapsing-remitting form. The se lective upregulation of MMP-9 suggests that T-cells and macrophages invadin g 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 upreg ulated or not detectable (MMP-7) in CSF of patients with relapsing-remittin g and primary progressive multiple sclerosis, The sustained increase of MMP -9 in clinically stable multiple sclerosis supports the concept that multip le sclerosis is associated with ongoing proteolysis that may result in prog ressive tissue damage. The selective inhibition of MMP-9 could be a useful approach for the prevention of disease progression in multiple sclerosis.