Matrix metalloproteinase inhibition reduces contraction by dupuytren fibroblasts.
OBJECTIVE
Dupuytren's disease is a common fibroproliferative condition of the hand characterized by fibrotic lesions (nodules and cords), leading to disability through progressive digital contracture. Although the etiology of the disease is poorly understood, recent evidence suggests that abnormal matrix metalloproteinase (MMP) activity may play a role in cell-mediated collagen contraction and tissue scarring. The aim of this study was to investigate the efficacy of ilomastat, a broad-spectrum MMP inhibitor, in an in vitro model of Dupuytren fibroblast-mediated contraction.


METHODS
Nodule-derived and cord-derived fibroblasts were isolated from Dupuytren patients; carpal ligament-derived fibroblasts acted as control. Stress-release fibroblast-populated collagen lattices (FPCLs) were used as a model of contraction. FPCLs were allowed to develop mechanical stress (48 hours) during treatment with ilomastat (0-100 micromol/L), released, and allowed to contract over a 48-hour period. Contraction was estimated by measuring lattice area compared with untreated cells or treatment with a control peptide. MMP-1, MMP-2, and MT1-MMP levels were assessed by zymography, Western blotting, and enzyme-linked immunosorbent assay.


RESULTS
Nodule-derived fibroblasts contracted lattices (69% +/- 2) to a greater extent than did cord-derived (55% +/- 3) or carpal ligament-derived (55% +/- 1) fibroblasts. Exposure to ilomastat led to significant inhibition of lattice contraction by all fibroblasts, although a reduction in lattice contraction by nodule-derived fibroblasts was most prominent (84% +/- 8). In addition, treatment with ilomastat led to a concomitant suppression of MMP-1 and MMP-2 activity, whereas MT1-MMP activity was found to be upregulated.


CONCLUSIONS
Our results demonstrate that inhibition of MMP activity results in a reduction in extracellular matrix contraction by Dupuytren fibroblasts and suggest that MMP activity may be a critical target in preventing recurrent contracture caused by this disease.
Townley
William A
WA
RAFT Institute of Plastic and Reconstructive Surgery, Mount Vernon Hospital, The Leopold Muller Building, Northwood, UK. willtownley@hotmail.com
Cambrey
Alison D
AD
Khaw
Peng T
PT
Grobbelaar
Adriaan O
AO
D000368:Aged; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen; D004387:Dupuytren Contracture / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D008875:Middle Aged; D015854:Up-Regulation
D006877:Hydroxamic Acids; D007211:Indoles; D061965:Matrix Metalloproteinase Inhibitors; D003094:Collagen; C119203:ilomastat