A complete expression profile of matrix-degrading metalloproteinases in Dupuytren's disease.
OBJECTIVE
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 reverse-transcription 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.
Johnston
Phillip
P
Institute of Orthopaedics, Norfolk and Norwich University Hospital, Norwich, UK.
Chojnowski
Adrian J
AJ
Davidson
Rose K
RK
Riley
Graham P
GP
Donell
Simon T
ST
Clark
Ian M
IM
D051722:ADAM Proteins / Q000378:metabolism; D000071096:ADAMTS Proteins; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004387:Dupuytren Contracture / Q000201:enzymology*; D005205:Fascia / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism
D019714:Tissue Inhibitor of Metalloproteinases; D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C447060:ADAMTS14 protein, human; D020782:Matrix Metalloproteinases; D020783:Matrix Metalloproteinase 7