Elsevier

Neuroscience

Volume 113, Issue 2, 12 August 2002, Pages 273-287
Neuroscience

Comparison of matrix metalloproteinase expression during Wallerian degeneration in the central and peripheral nervous systems

https://doi.org/10.1016/S0306-4522(02)00183-5Get rights and content

Abstract

The matrix metalloproteinases (MMPs) are a large family of zinc-dependent enzymes which are able to degrade the protein components of the extracellular matrix. They can be placed into subgroups based on structural similarities and substrate specificity. Aberrant expression of these destructive enzymes has been implicated in the pathogenesis of immune-mediated neuroinflammatory disorders. In this study we investigate the involvement of MMPs, from each subgroup, in Wallerian degeneration in both the central and peripheral nervous systems.

Wallerian degeneration describes the process initiated by transection of a nerve fibre and entails the degradation and removal of the axon and myelin from the distal stump. A similar degenerative process occurs as the final shared pathway contributing to most common neuropathies. MMP expression and localisation in the peripheral nervous system are compared with events in the CNS during Wallerian degeneration. Within 3 days after axotomy in the peripheral nervous system, MMP-9, MMP-7 and MMP-12 are elevated. These MMPs are produced by Schwann cells, endothelial cells and macrophages. The temporospatial expression of activated MMP-9 correlates with breakdown of the blood-nerve barrier.

In the CNS, 1 week after optic nerve crush, four MMPs are induced and primarily localised to astrocytes, not microglia or oligodendrocytes. In the degenerating optic nerve, examined at later time points (4, 8, 12 and 18 weeks), MMP expression was down-regulated. The absence of MMPs in oligodendrocytes and mononuclear phagocytes during Wallerian degeneration may contribute to the slower removal of myelin debris observed in the CNS. The low level of the inactive pro-form of MMP-9 in the degenerating optic nerve may explain why the blood-brain barrier remains intact, while the blood-nerve barrier is rapidly broken down.

We conclude that the difference in the level of expression, activation state and cellular distribution of MMPs may contribute to the different sequence of events observed during Wallerian degeneration in the peripheral compared to the CNS.

Section snippets

Wallerian degeneration

Adult Lewis rats obtained from Harlen Olac (Bicester, Oxon, UK), weighing 200–250 g at the beginning of the experiment, were used. During the study the rats were housed in cages of two or three animals and allowed access to food and water ad libitum. Animals were cared for in strict accordance with The Animals (Scientific Procedures) Act, 1986, under a Home Office license. All efforts were made to minimise both the suffering and the numbers of animals used. On day 0 the rats were anaesthetised

Results

The rate of loss of the axonal protein neurofilament-H (NF-H) and the myelin proteins, MBP and myelin-associated glycoprotein (MAG), was studied by immunohistochemistry during Wallerian degeneration in the rat sciatic and optic nerves. In corroboration with other studies (Bignami et al., 1981, Stoll et al., 1989b, George and Griffin, 1994), we found that during Wallerian degeneration in the sciatic nerve no NF-H immunostaining was detected by day 10 and that by day 15 all MBP- and MAG-positive

Discussion

In this study we have investigated the change in expression of 10 MMPs, representing each major subfamily, during the course of Wallerian degeneration in the rat nervous system. The morphological sequence of events that characterise Wallerian degeneration following nerve injury in the rat sciatic or optic nerve has been well defined; for example, see (Stoll et al., 1989a, Stoll et al., 1989b, George and Griffin, 1994, Perry et al., 1995). From this we can elucidate a potential role for the MMPs

Acknowledgements

We would like to thank the BBSRC (UK) and British Biotechnology Pharmaceuticals for support and the generous supply of excellent research tools.

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