MMPs and other matrix-degrading metalloproteinases in neurological disease

The metzincin superfamily of metalloproteinases includes the most well-studied matrix metalloproteinases (MMPs), the ADAMs (a disintegrin and metalloproteinase), and the ADAMTSs (ADAM with thrombospondin repeats) families of extracellular matrix (ECM)-degrading enzymes. These proteases are mostly secreted with important exceptions for the transmembrane sheddases and can degrade all protein components of the ECM. In addition to ECM proteins, secreted and cell-surface proteins including growth factors, cytokines, and chemokines may be cleaved by the MMPs. These proteases alter the composition and structural organization of the ECM; and importantly, cleavage affects intracellular signaling induced by binding of matrix molecules to cell-surface receptors. A body of data has been generated on the expression of these proteases in neurological disease, which is summarized here. In addition, the role of individual MMPs in particular animal models of disease has been investigated using genetically targeted mutant mice. In general, these results have suggested a detrimental role for the MMPs that relates to the induction of their expression in response to injury or disease.