title: MMP-14 and MMP-2 are key metalloproteases in Dupuytren's disease fibroblast-mediated contraction.
abstract: Dupuytren's disease (DD) is a common fibrotic condition of the palmar fascia, leading to deposition of collagen-rich cords and progressive flexion of the fingers. The molecular mechanisms underlying the disease are poorly understood. We have previously shown altered expression of extracellular matrix-degrading proteases (matrix metalloproteases, MMPs, and 'a disintegrin and metalloprotease domain with thrombospondin motifs', ADAMTS, proteases) in palmar fascia from DD patients compared to control and shown that the expression of a sub-set of these genes correlates with post-operative outcome. In the current study we used an in vitro model of collagen contraction to identify the specific proteases which mediate this effect. We measured the expression of all MMPs, ADAMTSs and their inhibitors in fibroblasts derived from the palmar fascia of DD patients, both in monolayer culture and in the fibroblast-populated collagen lattice (FPCL) model of cell-mediated contraction. Key proteases, previously identified in our tissue studies, were expressed in vitro and regulated by tension in the FPCL, including MMP1, 2, 3, 13 and 14. Knockdown of MMP2 and MMP14 (but not MMP1, 3 and 13) inhibited cell-mediated contraction, and knockdown of MMP14 inhibited proMMP-2 activation. Interestingly, whilst collagen is degraded during the FPCL assay, this is not altered upon knockdown of any of the proteases examined. We conclude that MMP-14 (via its ability to activate proMMP-2) and MMP-2 are key proteases in collagen contraction mediated by fibroblasts in DD patients. These proteases may be drug targets or act as biomarkers for disease progression.
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich Research Park, NR4 7TJ, UK.
authors.forename: Janine M
authors.initials: JM
authors.lastname: Wilkinson
authors.forename: Rose K
authors.initials: RK
authors.lastname: Davidson
authors.forename: Tracey E
authors.initials: TE
authors.lastname: Swingler
authors.forename: Eleanor R
authors.initials: ER
authors.lastname: Jones
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Corps
authors.forename: Phillip
authors.initials: P
authors.lastname: Johnston
authors.forename: Graham P
authors.initials: GP
authors.lastname: Riley
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Chojnowski
authors.forename: Ian M
authors.initials: IM
authors.lastname: Clark
mesh_terms: D002478:Cells, Cultured; D004387:Dupuytren Contracture / Q000378:metabolism* / Q000473:pathology; D005205:Fascia / Q000378:metabolism; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D053401:Palmar Plate / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering
chemical_list: D034741:RNA, Small Interfering; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1; D053511:Matrix Metalloproteinase 14