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.

SNPs Previously Associated with Dupuytren's Disease Replicated in a North American Cohort

“…8 Other studies identified the candidate genes MafB, MMPs, TGF-β, ADAM 12, POSTN, TNC, ADAMTS3, BMP5, collagenases, α-smooth muscle actin, fibronectin, β1 integrin, laminin, tenascin C, Hsp47, collagen 1, ALDH1A1, IRX6, PRG4, ZF9, PDGF-β, and c-myc. [15][16][17][18][19][20][21] Most recently, a whole genome-wide association study performed in Europe, identified eleven single nucleotide polymorphisms (SNPs) from nine different loci, with six of the loci known to be involved in the Wnt signaling pathway. 22 Because many genetic studies fail replication, and the findings may differ among populations of people, we set out to confirm these findings in a North American population.…”

MMP-2 Plays an Important Role During the Early Acute Developmental Phase of Oligofructose-Induced Equine Laminitis

“…Furthermore, activation of MMP-2 destroys the extracellular matrix and induces degradation of type IV collagen by collagenase, resulting in elevated levels of microvascular basement membrane permeability and deleterious structural changes (30) resulting from fluid leaking into the spaces created between the dermal and epidermal lamina. On the other hand, MMP-2 is the key protease in fibroblast-mediated collagen contraction (29) and MMP-2 is up-regulated as fibroblasts transition away from a myofibroblast phenotype (13).…”

Dupuytren’s contracture: the status and impact of collagenase Clostridium histolyticum treatment in Austria

“…Also, the impact of radiotherapy and shockwave therapy on Dupuytren's contracture has been investigated [14,[29][30][31][32]. A target for future therapies could be the dysregulation of IGF-II and IGFBP-6 in the development of Dupuytren's disease as well as metalloproteases [33,34].…”