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Nonproteolytic functions of matrix metalloproteinases in pathology and insights for the development of novel therapeutic inhibitors

Authors García-Pardo A, Opdenakker G

Received 24 January 2015

Accepted for publication 24 February 2015

Published 6 May 2015 Volume 2015:2 Pages 19—28


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Professor William Parks

Angeles García-Pardo,1 Ghislain Opdenakker2

1Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain; 2Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium

Abstract: Structural selectivity – in fact, the lack thereof – has been invoked as an explanation for the failure of matrix metalloproteinase (MMP) inhibitors as oncology drugs. However, functional selectivity is needed to develop a good drug. In addition, many drugs (including in oncology) act by interfering with signaling functions. The present market of successful biologicals contains many monoclonal antibodies, such as signaling inhibitors, with antitumor necrosis factor (anti-TNF) being the flagship of an armada. However, aside from its many pathogenic functions, TNF also plays physiological (ie, beneficial) roles. As long as the inhibition of detrimental functions supersedes the negative side effects, anti-TNF will be used. For such reasons, it is critical to know all the functions of MMPs, ideally before inhibitors are used as drugs. Here, we briefly summarize the known catalytic MMP functions and focus on the noncatalytic roles of these proteins, with an emphasis on their signaling effects. Indeed, recent studies have addressed the biology of multimolecular signaling complexes containing MMPs and the tissue inhibitors of metalloproteinases. These complexes are observed in solution (eg, as heteromers or homomultimers) and at the cell surfaces (eg, as docking complexes and signaling receptors). Consequently, a good understanding of the broader contexts – from the molecular, to the cellular and tissue levels – in which such molecular complexes operate will provide essential insights into direct new drug developments. This is exemplified with clinical and recent preclinical successes.

Keywords: MMPs, signaling pathways, PEX domain, noncatalytic function

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