Degradation of the extracellular matrix is crucial for a number of physiological and pathophysiological processes. Matrix metalloproteinases (MMPs) are a family of zinc-dependent neutral endopeptidases collectively capable of degrading and disrupting matrix components. This family which includes well over 20 metalloproteinases and endogenous inhibitors of the MMPs has been implicated in inflammatory diseases such chronic obstructive airway diseases (see our recent report on COPD), atherosclerosis, bone degenerative conditions including rheumatoid arthritis and osteoporosis, wound repair and, perhaps most well known, cancer. In this week's edition of TherapeuticAdvances, we highlight research from The Burnham Institute in La Jolla, CA investigating the role of MMPs in neurodegenerative diseases and stroke. Although MMPs are strongly implicated in the pathogenesis of these conditions, the mechanism of MMP activation remains unclear. This group reports that MMP activation involves S-nitrosylation. During cerebral ischemia in vivo, MMP-9 colocalized with neuronal nitric oxide synthase. S-Nitrosylation activated MMP-9 in vitro and induced neuronal apoptosis. Mass spectrometry identified the active derivative of MMP-9, both in vitro and in vivo, as a stable sulfinic or sulfonic acid, whose formation was triggered by S-nitrosylation. These findings suggest a potential extracellular proteolysis pathway to neuronal cell death in which S-nitrosylation activates MMPs, and further oxidation results in a stable posttranslational modification with pathological activity. Therefore, targeted prevention of the initial S-nitrosylation step may offer an alternative and perhaps more specific approach than the use of MMP inhibitors for the treatment of neurodegenerative diseases and stroke. Improved treatments would be welcome. Ischemic stroke affects about 600,000 Americans each year, 8% of whom die within 30 days. A further 15-30% are permanently disabled and 20% require institutional care. Direct and indirect costs of stroke are therefore immense. The treatment of ischemic stroke remains one of the most challenging areas of medicine today. At present, only thrombolysis is approved as a treatment strategy, and for only a brief window of time. Since many patients present far beyond this three-hour window, not surprisingly most patients receive only palliative care. In order to open the window of therapeutic opportunity, the pharmaceutical industry is currently focusing on the development of new opportunities and inhibiting MMP activity would be appealing in this respect. Alzheimer's disease is also very common, affecting four million Americans, and experts estimate that 22 million people around the world will be so afflicted by 2025. Hence, if preventing the S-nitrosylation of MMP-9 can limit the development of Alzheimer's or post-stroke ischemia, this field could become of major clinical and commercial importance.

Entry date September, 2002

Adapted from Gu et al, Science 2002 Aug 16;297(5584):1186-90

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