THE ROLE OF MATRIX-METALLOPROTEINASES AND THEIR INHIBITORS IN DUPUYTREN’S CONTRACTURE

Abstract

Dupuytren’s contracture (DC) is a non-lethal disabling disease, characterised by a progressive fibrosis of the deep palmar fascia, produced by an increased deposition of collagen within the extracellular matrix (ecm). Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that degrade ecm proteins. Their activity is regulated by growth factors, cytokines and by specific tissue inhibitors (TIMPs). An imbalance in the normal relationship between expression of MMPs and TIMPs is believed to contribute to the pathogenesis of other fibroproliferative diseases.

We have performed a detailed immunohistochemical analysis of DC tissue which provides the most comprehensive profile to date of the MMP and TIMP expression in DC. Sections were immunostained using antibodies against a panel of MMPs and TIMPs. Normal palmar fascia from patients undergoing carpal tunnel release or from cadaveric hands was used as controls.

There was a marked increase in the expression of MMPs and TIMPs within the different areas of DC tissue compared with controls. Both MMPs and TIMPs were expressed in an angiocentric pattern within areas of hypercellularity (corresponding to the proliferative stages of nodules). In some hypercellular areas expression of TIMP1 and TIMP2 exceeded that for the MMPs. Hypocellular cords, which were predominantly composed of collagen, were weakly immunopositive for MMP-2 and MMP-9, but were immunonegative for TIMPs.

Areas of MMP-1 and MMP-2 expression were more intense in the stroma surrounding nodules, and also within the “invading” DC tissue at the dermo-epidermal junction (DEJ) of the skin. Here expression of MMPs was observed around abnormally high numbers of small blood vessels, beneath the rete ridges of the epidermal layer, and also within foci of inflamation.TIMP1 and TIMP-2 were not expressed within the DEJ. These changes were most marked where clinically there was obvious ‘skin pit’ involvement.

Currently the only treatment for DC is surgical. Alternative non-surgical therapeutic protocols might involve manipulating the fibrotic process pharmacologically, for example by seeking to regulate expression of MMPs and their inhibitors.