MMPs made easy

09/11/09 | Assessment and diagnosis, Complex wounds, Diabetic foot ulcers | D Gibson D, B Cullen, R Legerstee, Harding KG and Schultz G.

MMPs made easyThis article describes what MMPs are and the importance of their role in normal and disrupted wound healing. It discusses the relevance of MMPs to clinical practice, including content and potential interventions aimed at modulating their activity

INTRODUCTION

This article describes what MMPs are and the importance of their role in normal and disrupted wound healing. In particular, it discusses the relevance of MMPs to clinical practice, including current and potential interventions aimed at modulating their activity.

 

WHAT ARE MMPs?

The matrix metalloproteinases (MMPs) are part of the larger family of metalloproteinase enzymes that play an important part in wound healing [1,2].

Enzymes are proteins that facilitate biological reactions, but are not themselves used up or changed in the reactions. They generally act on a limited number of molecules (known as the enzymes' substrates) and physically change them into other substances. Proteinases (also known as proteases) are enzymes that act on proteins, usually by cutting up the protein molecule.

Natural substrates for the different MMPs vary substantially, but include important extracellular matrix (ECM) proteins such as collagen, gelatin and proteoglycans. The MMPs degrade these proteins by cutting them into pieces. Different MMPs may act sequentially and on different parts of the same substrate.

 

Why are they called matrix metalloproteinases?

The name 'matrix metalloproteinase' (or 'matrix metalloprotease') indicates the key properties shared by the MMPs. They all:

  • preferentially breakdown proteins comprising the extracellular matrix of tissues
  • require a metal ion (zinc) at the active centre of the enzyme.

 

HOW ARE MMPs PRODUCED?

In normal wound healing, MMPs are produced by:

  • activated inflammatory cells (neutrophils and macrophages)
  • wound cells (epithelial cells, fibroblasts and vascular endothelial cells).

When first synthesised, MMPs are in a latent (inactive or pro-MMP) form. They are activated by other proteases that clip off a short section of the molecule. This opens up the active centre of the MMP molecule and allows the MMP to bind to its protein substrate(s). Other molecules called 'tissue inhibitors of metalloproteinases' (TIMPs) can inhibit activated MMPs and block the activation of pro-MMPs (Fig 1).

Figure 1

So far, 23 human MMPs have been identified. MMP-1, MMP-2, MMP-8 and MMP-9 have been the particular focus of research in relation to wounds. While most MMPs are secreted into the surrounding ECM, some MMPs remain associated with cell membranes, and are known as 'membrane-type' MMPs (MT-MMPs). This group of MMPs is thought to play an important role in activating pro-MMPs, as well as activating pro-TNF (tumour necrosis factor - an important mediator involved in inflammation and cell death).