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  • Review Article
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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. However, the potential use of metalloproteinase inhibitors in chronic conditions such as multiple sclerosis should be approached with caution, because of the beneficial roles of metalloproteinases in some of the repair processes.

  • Significant challenges still lie ahead with respect to modulating metalloproteinase functions in development and following an insult or in disease. Nonetheless, studies of CNS regeneration must consider the metalloproteinases, given their multitude of beneficial and detrimental functions in the nervous system.

Abstract

The matrix metalloproteinases and related A disintegrin and metalloproteinase enzymes are implicated in various diseases of the nervous system. However, metalloproteinases are increasingly being recognized as having beneficial roles during nervous system development and following injury. This review discusses general principles that govern the expression of metalloproteinases in the nervous system and their detrimental outcomes. It then focuses on the roles of metalloproteinases and their mechanisms in regulating neurogenesis, myelin formation and axonal growth. It is clear that metalloproteinases are important determinants in enabling recovery from injury to the nervous system.

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Figure 1: Structure of matrix metalloproteinases and A disintegrin and metalloproteinases.
Figure 2: Interactions between metalloproteinases, cytokines, chemokines and other molecules present at a site of injury and their consequences.
Figure 3: The metalloproteinases regulate developmental and regenerative events in the CNS.
Figure 4: Mechanisms by which metalloproteinases might regulate axonal regeneration of neurons.
Figure 5: Metalloproteinases regulate myelinogenesis.
Figure 6: Multiple ways of targeting the metalloproteinases.

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Acknowledgements

The author wishes to thank the numerous trainees who worked on metalloproteinase biology while in the Yong laboratory. A grateful acknowledgement is also due to funding agencies, particularly the Canadian Institutes of Health Research and the Multiple Sclerosis Society of Canada. The author thanks R. Nuttall, A. Fournier and D. Edward for reading through parts of this manuscript, and F. Yong for help with the figures.

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DATABASES

Entrez Gene

ADAM10

ADAM12

ADAM13

ADAM23

ADAMTS14

kuzbanian

MMP2

MMP3

MMP7

MMP9

MMP14

MMP26

TIMP1

TIMP2

TIMP3

UNC-17

OMIM

multiple sclerosis

Glossary

INTEGRINS

Receptors on cells that interact with ECM proteins or other cell surface molecules, and that regulate important functions such as growth and survival.

ZYMOGEN

An inactive pro-form of an enzyme. All metalloproteinases are initially expressed as zymogens that require processing to expose their active catalytic site.

ECTODOMAIN SHEDDING

Refers to the release of an active factor from the cell membrane, usually from an inactive form, by proteases. For instance, all EGF receptor ligands, which affect development and disease, are released in this manner.

GELATIN ZYMOGRAPHY

A gel-based method, using gels impregnated with gelatin, to measure the level of MMP2 and MMP9 through their ability to degrade gelatin.

EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS

(EAE). An animal model of multiple sclerosis that is initiated in animals by injecting myelin proteins or peptides to raise autoreactive T cells, or by the transfer of autoreactive T cells into naive recipients.

CHEMOKINES

A subfamily of inflammatory molecules that were initially described in regulating the chemotaxis of inflammatory cells, but that also have important roles in other processes, such as cell growth and differentiation.

CHONDROITIN SULPHATE PROTEOGLYCANS

(CSPGs). Important components of the ECM. The deposition of these proteins at sites of CNS injury is an important impediment to axonal regrowth.

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Yong, V. Metalloproteinases: Mediators of Pathology and Regeneration in the CNS. Nat Rev Neurosci 6, 931–944 (2005). https://doi.org/10.1038/nrn1807

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