Review
MMPs as therapeutic targets—Still a viable option?

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Abstract

Matrix metalloproteinases (MMPs) appear to be ideal drug targets—they are disease-associated, extracellular enzymes with a dependence on zinc for activity. This apparently straightforward target, however, is much more complex than initially realized. Although disease associated, the roles for particular enzymes may be healing rather than harmful making broad-spectrum inhibition unwise; targeting the catalytic zinc with specificity is difficult, since other related proteases as well as non-related proteins can be affected by some chelating groups. While the failure of early-generation MMP inhibitors dampened enthusiasm for this type of drug, there has recently been a wealth of studies examining the basic biology of MMPs which will greatly inform new drug trials in this field.

Introduction

As we have seen from accompanying papers, there is considerable evidence implicating MMP activity in various pathologies including cancer, diseases of the central nervous system (CNS) and disorders of the immune system. Given the many physiological processes that are controlled by MMP activity, it is unsurprising that aberrant proteolysis is a significant problem in multiple disease settings. Studies using relevant disease models in MMP-deficient animals have demonstrated the contribution of MMPs to disease processes. These studies have, however, revealed some surprising, apparently protective functions of various MMP family members. Hence broad-scale MMP inhibition can have both advantageous and problematic consequences. Here we will examine some of these as well as the settings in which inhibiting MMPs can be a successful therapeutic approach. As many readers will be aware, pharmacological MMP inhibitors (MMPIs) have failed in multiple clinical trials [1], [2]. However, we believe that these failures should not define the field and will suggest ways in which future iterations of MMPIs could potentially be of significant therapeutic benefit.

Section snippets

Evidence for targeting MMPs

Proteolysis is a very effective mechanism for introducing diversity into the protein complement of an organism. Unlike many other modifications, however, this is an irreversible change. For this reason, although proteases are a major group within the proteome [3], activity levels of proteases such as MMPs are tightly controlled [4]. This is logical since rampant proteolysis would not be an efficient way to maintain homeostasis. In disease settings, however, the expression levels of individual

Animal models

Expression analyses provide evidence that a protein target is present at high levels when a disease is manifest and, ideally, absent in the healthy state. However, these types of studies cannot determine whether the presence of the particular protein is in any way associated with the disease process or whether it is merely an ancillary event. Using animal models in which expression can be manipulated provides some evidence for the contributory effect of the particular protein to the disease

Limitations of animal models

Although studies in MMP-deficient animals are highly suggestive of roles for MMPs in various disease processes, there are some caveats to be aware of. Firstly, as previously noted, most of the MMP-null animals are constitutively null. Hence some of the apparent effects of deficiency apparent in pathological situations may be reflective of an altered physiology that developed as a way to circumvent the MMP deficiency, thus the differing effect seen in the null animal is not actually due to the

Are there situations where MMPs should not be targeted?

When the idea of pharmacological agents that would inhibit MMP function was first suggested, there was a basic assumption that MMPs contributed detrimental activities. Therefore inhibition would be favorable. A significant finding from multiple mouse studies is that MMPs can also be beneficial. This of course should not be surprising as it would not be evolutionarily favorable for development of an entire family of proteases that are only detrimental to an organism! Rather than categorizing

Reasons for non-efficacy of early MMPIs

One of the biggest questions regarding the original MMP inhibitor clinical trials was how they could fail to show any efficacy despite data from multiple animal models suggesting they would be useful [1], [2]. Of course there are always the problems of extrapolating models to the human disease setting. As discussed previously, the animal models are usually concerned with specific disease processes rather than the overwhelming sum of processes that can be present in a human patient.

Conclusion

Overwhelming evidence from animal models strongly suggests a number of therapeutic areas that would benefit from MMP inhibition. These include various cancers, cardiac remodeling post infarction, chronic obstructive pulmonary diseases, cerebral ischemia, multiple sclerosis and certain skin and eye diseases [108]. The latter two settings have the advantage of allowing local, non-systemic delivery thus potentially avoiding the MSS side effects that have plagued clinical trials of orally dosed

Acknowledgements

The author would like to acknowledge the Susan G. Komen Foundation (BCTR0600431) for funding. Apologies to the many authors whose work could not be mentioned due to space limitations.

References (33)

  • N.P. Kadoglou et al.

    Matrix metalloproteinases: contribution to pathogenesis, diagnosis, surveillance and treatment of abdominal aortic aneurysms

    Curr Med Res Opin

    (2004)
  • A.C. Newby

    Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture

    Physiol Rev

    (2005)
  • M.L. Lindsey

    MMP induction and inhibition in myocardial infarction

    Heart Failure Rev

    (2004)
  • R.E. Chapman et al.

    Extracellular protease activation and unraveling of the myocardial interstitium: critical steps toward clinical applications

    Am J Physiol Heart Circ Physiol

    (2004)
  • A.M. Deschamps et al.

    Matrix modulation and heart failure: new concepts question old beliefs

    Curr Opin Cardiol

    (2005)
  • L.A. Cunningham et al.

    Multiple roles for MMPs and TIMPs in cerebral ischemia

    Glia

    (2005)
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