Review
Matrix metalloproteinases: multifunctional effectors of inflammation in multiple sclerosis and bacterial meningitis

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Abstract

Matrix metalloproteinases (MMPs) are a family of Zn2+-dependent endopeptidases targeting extracellular matrix (ECM) compounds as well as a number of other proteins. Their proteolytic activity acts as an effector mechanism of tissue remodeling in physiologic and pathologic conditions, and as modulator of inflammation. In the context of neuro-inflammatory diseases, MMPs have been implicated in processes such as (a) blood–brain barrier (BBB) and blood–nerve barrier opening, (b) invasion of neural tissue by blood-derived immune cells, (c) shedding of cytokines and cytokine receptors, and (d) direct cellular damage in diseases of the peripheral and central nervous system. This review focuses on the role of MMPs in multiple sclerosis (MS) and bacterial meningitis (BM), two neuro-inflammatory diseases where current therapeutic approaches are insufficient to prevent severe disability in the majority of patients. Inhibition of enzymatic activity may prevent MMP-mediated neuronal damage due to an overactive or deviated immune response in both diseases. Downregulation of MMP release may be the molecular basis for the beneficial effect of IFN-β and steroids in MS. Instead, synthetic MMP inhibitors offer the possibility to shut off enzymatic activity of already activated MMPs. In animal models of MS and BM, they efficiently attenuated clinical disease symptoms and prevented brain damage due to excessive metalloproteinase activity. However, the required target profile for the therapeutic use of this novel group of compounds in human disease is not yet sufficiently defined and may be different depending on the type and stage of disease. Currently available MMP inhibitors show little target-specificity within the MMP family and may lead to side-effects due to interference with physiological functions of MMPs. Results from human MS and BM indicate that only a restricted number of MMPs specific for each disease is up-regulated. MMP inhibitors with selective target profiles offer the possibility of a more efficient therapy of MS and BM and may enter clinical trials in the near future.

Section snippets

The matrix metalloproteinase family and related metalloproteinases

The MMPs comprise a family of over 20 endopeptidases that serve as effectors of cell migration, cytotoxicity and tissue remodeling via degradation of extracellular matrix (ECM) components (Table 1). MMPs are products of different genes, but show a high degree of homology due to their modular domain structure (Fig. 1) (for review, see Ref. [64]). The core domain contains two Zn2+ ions, of which one acts as catalytic principle, hence the name ‘metallo’. Besides Zn2+, the catalytic activity is

Physiologic and pathologic functions of MMPs

The first MMP, interstitial collagenase (MMP-1), was described in 1962 [16] on the basis of its function for the resorption of tail collagen stroma in the metamorphosis of tadpoles. Since then, MMPs were shown to be involved in almost all processes of ontogeny: MMPs regulate ovulation and uterine tissue remodeling during the menstrual cycle, mediate embryo nidation and later regulate tissue remodeling during morphogenesis and growth. In adult organisms, MMP expression is generally low and only

Regulation of MMPs

The net effect of a mixture of MMPs in a tissue compartment is determined by their concentrations which is a function of the cellular source and of active stimuli, their spatial distribution, and the levels of regulatory proteins. Similar to other highly active, enzyme-based systems (e.g. the blood clotting cascade), the activity of MMPs is tightly regulated to prevent excessive proteolytic activity, and hence tissue destruction. Under physiologic conditions, the action of MMPs is regulated on

Synthetic inhibitors of MMPs

In recent years, synthetic low molecular weight, hydroxamic acid based MMP-Is have been developed and clinical testing of these novel compounds has begun in patients with cancer, rheumatoid arthritis, corneal ulcers, among other diseases [63]. The past years have seen a number of disappointments with the halting of clinical trials in these diseases for several reasons. In several types of human cancer MMP-Is failed to confirm the inhibitory effect on tumour progression as observed in animal

MMPs in multiple sclerosis and EAE

MS is considered as a chronic autoimmune disorder of the central nervous system (CNS) leading to progressive dysfunction in motor, sensory and vegetative systems, and eventually severe disability in the majority of patients [43]. Patho-anatomically, MS is characterised by recurrent focal BBB damage, perivascular lymphocyte infiltration and patchy degradation of myelin, leading to the formation of gliotic lesions (plaques), and eventually to axonal disruption. There is accumulating evidence that

MMPs in bacterial meningitis

Bacterial meningitis (BM) continues to be an important clinical problem, as both mortality and the incidence of neurological deficits remain at an unacceptable high level of incidence despite effective antimicrobial therapy [29]. An overactive immune response of the host, rather than the bacterial pathogen per se is thought to be responsible for the brain damage, resulting in neurological sequelae including hearing loss, secondary epilepsy and cognitive impairment [30]. Two distinctive forms of

Conclusions and open questions

MMPs are effectors of BBB opening and invasion of brain parenchyma by immune cells in MS and BM. In addition they can act, together with related metalloproteinases, as enhancers of the immune response via their proteolytic release of membrane-bound cytokines and their receptors. Hydroxamic acid type MMP-Is have been used successfully in animal models of MS and BM to attenuate acute disease symptoms and structural damage of the brain parenchyma; in BM they were able to attenuate postmeningitidal

Acknowledgements

This work was supported by grants from the Swiss National Science Foundation (4038-52841, 31-51084.97 and 32-61654.00), the NIH (US) (NS-35902), the Swiss Multiple Sclerosis Society, the Meningitis Research Foundation (UK), the Schering Foundation, the Théodore Ott Fonds, the Margarete and Walter Lichtenstein Foundation, and Swiss Life Insurance.

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