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Title: The progression from contraction to contracture in Dupuytren's derived fibroblasts : a study of the cellular and molecular events
Author: Beckett, Kate
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2006
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Abstract:
Dupuytren's disease is a debilitating fibroproliferative disorder of the palmar fascia affecting hand function. Clinically the appearance of nodules and cords is characterised by the deposition of excess extracellular matrix within the fascia. Progressive shortening of the matrix leads to increased stiffness and permanent tissue contracture. Surgical release of contracture is the only current treatment but despite this, recurrence rates are high. It has been postulated that contracture is a result of two separate processes occurring in parallel: a) Cell mediated contraction of the matrix - whereby fibroblasts act to cause a physical deformation within the resident tissue (Harris et al 1981), and b) Continuous matrix remodelling, leading to the permanence of contracture (Flint and Poole 1990 Tomasek et al 2002). A culture force monitor model was used to study the contractile properties of fibroblasts cultured in three dimensional collagen gels. Dupuytren's nodule and cord fibroblasts generated significantly greater forces in comparison to carpal ligament fibroblasts (p<0.001), and similar forces in comparison to dermal fibroblasts over a 48 hour period. Carpal ligament and dermal fibroblasts reached tensional homeostasis by 24 hours showing no further increase in contraction. Dupuytren's fibroblasts continued to contract with no plateau at 24 or 48 hours (jX 0.001). A reduction in external load applied to these fibroblasts resulted in an increase in cellular contraction by both Dupuytren's and control fibroblasts. Baseline tissue inhibitor of matrix metalloproteinase (TIMP) expression in both Dupuytren's and control fibroblasts without external mechanical stimulation was significantly greater than that of the matrix metalloproteinases (MMPs). There was no difference in expression between carpal ligament and Dupuytren's fibroblasts. Mechanical stimulation resulted in a significant up-regulation of MMP gene expression by Dupuytren's nodule fibroblasts (jXO.01). There was no up-regulation of MMPs by cord or carpal ligament derived fibroblasts. There was a reciprocal significant up- regulation of TIMP-1 expression by carpal ligament derived cells after mechanical stimulation (p<0.001), with a similar response by cord derived cells (p<0.005). This response was absent in nodule derived fibroblasts. The amount of permanent shortening of a collagen matrix, the residual matrix tension (RMT), was quantified over a 48 hour period using the culture force monitor model. Over a short time period residual matrix tension was minimal following disruption of the actin cytoskeleton by cytochalasin-D in all fibroblasts under investigation, indicating that no spatial remodeling of the collagen had occurred. However by 48 hours a permanent shortening of the collagen network was seen which was most marked for Dupuytren's and dermal fibroblasts, and which was significantly greater than that for carpal ligament fibroblasts (p<0.05). In summary, there appears to be a primary abnormality in the process of cellular contraction, leading to the progression of contracture seen in Dupuytren's disease. It is postulated that cellular contraction holds the matrix in a newly shortened state, while concurrently the cells act to remodel the surrounding matrix to hold it there permanently.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.423093  DOI: Not available
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