A Complete Expression Profile of Matrix-Degrading Metalloproteinases in Dupuytren’s Disease

Abstract

Purpose: Dupuytren's disease (DD) is a common fibrotic condition of the palmar fascia, leading to deposition of collagen-rich cords and finger contractions. The metzincin superfamily contains key enzymes in the turnover of collagen and other extracellular matrix macromolecules. A number of broad-spectrum matrix metalloproteinase inhibitors, used in cancer clinical trials, caused side effects of DD-like contractures. We tested the hypothesis that changes in the expression of specific metalloproteinases underlie or contribute to the fibrosis and contracture seen in DD. Methods: We collected tissue from patients with DD and used normal palmar fascia as a control. We profiled the expression of the entire matrix metalloproteinase (MMP), tissue inhibitor of metalloproteinases (TIMP), and a disintegrin and metalloproteinase domain with thrombospondin motif (ADAMTS) gene families in these tissues using real-time reversetranscription polymerase chain reaction. Results: A number of metalloproteinases and inhibitors are regulated in DD. The expression of 3 key collagenases, MMP1, MMP13, and MMP14 is increased significantly in the DD nodule, as is the expression of the collagen biosynthetic enzyme ADAMTS14. The expression of MMP7, an enzyme with broad substrate specificity, is increased in the DD nodule and remains equally expressed in the DD cord. TIMP1 expression is increased significantly in DD nodule compared with normal palmar fascia. Conclusions: This study measured the expression of all MMP, ADAMTS, and TIMP genes in DD. Contraction and fibrosis may result from: (1) increased collagen biosynthesis mediated by increased ADAMTS-14; (2) an increased level of TIMP-1 blocking MMP-1-and MMP-13-mediated collagenolysis; and (3) contraction enabled by MMP-14 -mediated pericellular collagenolysis (and potentially MMP-7), which may escape inhibition by TIMP-1. The complete expression profile will provide a knowledge-based approach to novel therapeutics targeting these genes. (J Hand Surg 2007;32A:343-351.

Matrix Metalloproteinase Inhibition Reduces Contraction by Dupuytren Fibroblasts

“…Elevated levels of MMP-1 mRNA in Dupuytren-derived nodule have also been observed in palmar aponeurosis. 31 In our study, treatment with ilomastat inhibited enzymic activity of MMP-1 in Dupuytrenderived fibroblasts (both nodule and cord) whereas levels of secreted MMP-1 protein were unaffected. These results imply utilization of MMP-1 during matrix FIGURE 6: Analysis of gelatinolytic activity produced in conditioned media collected from stressed (before release) and contracting (after release) collagen lattices.…”

“…These results suggest that MMP-2 activation occurred concomitantly with lattice contraction supporting an important role for MMP-2 in processing and remodeling of the collagen lattice by Dupuytren fibroblasts. Elevated levels of active MMP-2 have also been observed in actively remodeling palmar aponeurosis of Dupuytren patients 31,32 ; specifically, nodules and cords exhibited the highest MMP-2 levels compared with normal palmar fascia. 31 In this study, ilomastat treatment inhibited activity of MMP-2 in all fibroblast cell strains.…”

“…Elevated levels of active MMP-2 have also been observed in actively remodeling palmar aponeurosis of Dupuytren patients 31,32 ; specifically, nodules and cords exhibited the highest MMP-2 levels compared with normal palmar fascia. 31 In this study, ilomastat treatment inhibited activity of MMP-2 in all fibroblast cell strains. MMP-1 is involved in proteolytic cleavage of the triple helical structure of type I collagen, exposing fragments that are susceptible to gelatinases including MMP-2.…”

Myofibroblast Distribution in Dupuytren's Cords: Correlation With Digital Contracture

“…This would be supported by the increased expression of matrix metalloproteinases in Dupuytren's nodules and cord. [23][24][25][26] The resulting increased flexion deformity would impair function and the reduced movement at the joint would in turn lead to a reduction in tension sensed by nodular myofibroblasts. This can be considered as a form of stress shielding, which in wound healing has been shown to result in myofibroblast apoptosis after re-epithelialization.…”

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…The expression of MMP-7 is increased in the DD nodule and remains equally expressed in the DD cord (Johnston et al, 2007).…”