title: The mechanical environment in Dupuytren's contracture determines cell contractility and associated MMP-mediated matrix remodeling.
abstract: Matrix metalloproteinases (MMPs) are expressed in Dupuytren's contracture and play a role in matrix remodeling. We tested the role of tension on contractility and MMP expression in Dupuytren's nodule and cord cells. Cells were subjected to pre-determined loading patterns of known repeatable magnitudes (static load, unloading, and overloading) and tested for MMP gene expression (MMP-1, -2, -9, -13, and TIMP-1, -2) and force generation using a tension-culture force monitor. Matrix remodeling was assessed by addition of cytochalasin D and residual matrix tension was quantified. Nodule compared to cord and control cells demonstrate greater force generation and remodeling (p < 0.05). Nodule cells subjected to a reduced load and overloading led to threefold increase of MMP-1, -2, and -9 compared to static load, whilst cord and control cells only showed a twofold increase of MMP-9. Nodule cells subjected to overloading showed a twofold increase in TIMP-2 expression, whilst cord and control cells showed a twofold increase in TIMP-1 expression. Nodule cells differ from cord cells by increased force generation in response to changes in the mechanical environment and related MMP/TIMP-mediated matrix remodeling. In turn this may lead to permanent matrix shortening and digital contracture. Interventional therapies should be aimed at nodule cells to prevent contraction and subsequent permanent matrix remodeling.
authors.affiliation: Institute of Orthopaedics and Musculoskeletal Sciences, University College London, Stanmore, United Kingdom. jsn.verhoekx@gmail.com
authors.forename: Jennifer S N
authors.initials: JS
authors.lastname: Verhoekx
authors.forename: Kate S
authors.initials: KS
authors.lastname: Beckett
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Bisson
authors.forename: Duncan A
authors.initials: DA
authors.lastname: McGrouther
authors.forename: Adriaan O
authors.initials: AO
authors.lastname: Grobbelaar
authors.forename: Vivek
authors.initials: V
authors.lastname: Mudera
mesh_terms: D000368:Aged; D002478:Cells, Cultured; D015638:Cytochalasin D / Q000494:pharmacology; D004387:Dupuytren Contracture / Q000503:physiopathology*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D015870:Gene Expression; D006801:Humans; D020782:Matrix Metalloproteinases / Q000096:biosynthesis*; D008875:Middle Aged; D009119:Muscle Contraction; D013314:Stress, Mechanical; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis
chemical_list: C560822:TIMP1 protein, human; C560823:TIMP2 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D015638:Cytochalasin D; D020782:Matrix Metalloproteinases