Metalloproteinases: Mediators of Pathology and Regeneration in the CNS

Key Points The matrix metalloproteinases (MMPs) and A disintegrin and metalloproteinases (ADAMs) are expressed in the healthy nervous system, although many of them are significantly upregulated in disease and injury states. The substantial upregulation of several metalloproteinases is detrimental and contributes to neuroinflammation and neuropathology in diseases and insults, including multiple sclerosis, stroke and spinal cord injury. This review discusses some of the general functions of metalloproteinases in mediating responses to neurological disease state. It highlights the interactions of metalloproteinases with other molecules found at injury sites, such as chemokines and nitric oxide, which generate products that have profound effects on the nervous system. In contrast to their detrimental functions, it is now clear that some metalloproteinases have beneficial roles during development and after injury to the adult nervous system. This review summarizes the evidence and discusses the mechanisms by which metalloproteinases regulate neurogenesis, axonal guidance and growth in neural development. In response to injury, and following the initial abnormal upregulation of several metalloproteinases, some metalloproteinases are expressed very locally at particular sites at specific time points after the insult. Often, the levels of these discretely expressed metalloproteinases are low and difficult to detect with gel-based approaches. In these circumstances, these metalloproteinases might participate in the repair process. This review discusses the data suggesting that MMPs are involved in axonal regeneration, and evaluates some of the attendant mechanisms. The latter includes interference with inhibitors of axonal regrowth, which are present in CNS myelin, including Nogos. The clearance of inhibitory extracellular matrix proteins constitutes another mechanism by which metalloproteinases regulate axonal regrowth. Metalloproteinases also participate in the remyelination process following injury, and the evidence for this is reviewed here. In view of the beneficial and detrimental roles of metalloproteinases, this review discusses the determinants through which the different outcomes are achieved. We speculate that acute neurological diseases and insults, including stroke and spinal cord injury, are amenable to treatment with metalloproteinase inhibitors, given that the acute upregulation of several metalloproteinases leads to significant neuropathology. How