Elsevier

Biochimie

Volume 166, November 2019, Pages 223-232
Biochimie

Review
Matrix metalloproteinase-2: Not (just) a “hero” of the past

https://doi.org/10.1016/j.biochi.2019.07.019Get rights and content

Highlights

  • Key features of matrix metalloproteinase-2 (MMP-2) are reviewed.

  • MMP-2 inhibition in cancer failed due to detrimental side effects.

  • MMP-2 remains attractive, notably as a diagnostic or prognostic tool.

Abstract

The 72-kDa type IV collagenase or gelatinase A is the second member of the matrix metalloproteinase family, MMP-2. Since the discovery of its first two substrates within components of the extracellular matrix, denatured interstitial type I collagen and native type IV collagen, the roles and various levels of regulation of MMP-2 have been intensively studied, mainly in vitro. Its (over)expression in most if not all tumors was considered a hallmark of cancer aggressiveness and boosted investigations aiming at its inhibition. Unfortunately, the enthusiasm subsided like a soufflé after clinical trial failures, mostly because of insufficient knowledge of in vivo MMP-2 activities and detrimental side effects of broad-spectrum MMP inhibition.

Nowadays, MMP-2 remains a major topic of interest in research, the second in the MMP family after MMP-9. This review presents a broad overview of the major features of this protease. This knowledge is crucial to identify diagnostic or therapeutic strategies focusing on MMP-2. In this sense, recent publications and clinical trials underline the potential value of measuring circulating or tissular MMP-2 levels as diagnostic or prognostic tools, or as a useful secondary outcome for therapies against other primary targets. Direct MMP-2 inhibition has benefited from substantial progress in the design of more specific inhibitors but their in vivo application remains challenging but certainly worth the efforts it receives.

Introduction

This minireview is not intended to present an extensive review on matrix metalloproteinase (MMP)-2. The purpose is to give an overview of key features of the two lives of MMP-2. Its first life (1980's – 1990's) was rich in biochemical characterization: structure, substrates, regulation, mechanisms of activation and inhibition … But most importantly, MMP-2 emerged as a key player in cancer invasion and metastasis, triggering a craze for strategies aiming at its in vivo inhibition. Unfortunately, adverse effects of broad spectrum MMP inhibitors (i.e. due to beneficial effects of MMPs) almost rang the bell for the whole field. However, MMP-2, like its close relative MMP-9, still continues to benefit from a sustained interest, as illustrated by the number of publications focusing on, or related with these two MMPs during the last five years (Fig. 1). This second life of MMP-2 (2000's and 2010's) is clearly focused on two major topics: a better knowledge of its precise functions in vivo and in pathologies, and the design of more specific inhibitors devoid of adverse effects.

In this minireview, we will summarize key features of MMP-2, in a rather historical (and nostalgic) approach, referring to seminal observations and/or outstanding reviews and we will also give a brief overview of the ongoing research.

Section snippets

Discovery

In the early 1970's, Harris and Krane identified in the rheumatoid synovial tissue culture medium an endopeptidase degrading the denatured form of type I collagen or gelatin, but not its native form [1]. By analogy with a previously described endopeptidase called collagenase because of its catalytic activity against native type I collagen [2], the gelatin-degrading enzyme was termed gelatinase. The gelatinase was then purified in a latent 72-kDa form from culture media of various tissues and

Biochemical and biological features

MMP-2 is a Zn2+-dependent enzyme encoded by a gene located on the long arm of chromosome 16 at position q12.2. The 27 kb-long MMP2 gene has 13 exons [8] and is classically transcribed in a 3.1 kb-mRNA [4]. The cDNA for MMP-2 codes for a 660 residues preproenzyme containing a 29 residues signal peptide responsible for translocation to the endoplasmic reticulum and followed by the 72-kDa-proenzyme (Fig. 2). ProMMP-2 is composed of a propeptide followed by a catalytic domain that is connected to a

Pathologies

From the first correlation established between metastatic potential and degradation of basement membrane type IV collagen by a 65-kDa endopeptidase [139] up to the discovery of MT1-MMP [140], MMP-2 overexpression was considered as a hallmark of cancer aggressiveness. Meta-analyses found that MMP-2 expression could be correlated (and often proposed to be used as prognostic marker) with pituitary adenomas [141], breast cancer [142], ovarian cancer [143], endometrial cancer [144], gastric cancer [

Perspectives and conclusion

As our knowledge progresses, the original “gelatinase”, described as being able to degrade denatured interstitial type I collagen, has grown considerably in importance. In this sense, it has followed the same route as other members of the MMP family: from basic proteinases degrading components of the extracellular matrix, they have become major actors with extra-, peri- and intra-cellular functions. As a predictable consequence, they have been implicated in many pathologies. In particular,

Funding sources

This work was supported by grants from the Fonds de la Recherche Scientifique (F.R.S.-FNRS, Belgium) to P.H. (Research Associate at F.R.S.-FNRS), and from the Université de Reims Champagne-Ardenne (URCA) and the Centre National de la Recherche Scientifique (CNRS, France) to H.E.

Conflict of interest

We have no conflict of interest to declare.

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