Bisson, M.; (2004) The contractile properties of fibroblasts derived from Dupuytren's nodules and cords and the effect of TGF-b stimulation. Doctoral thesis , University of London.

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Abstract

Dupuytren's disease is a common fibroproliferative disorder with digital flexion deformities causing disability. Two forms are apparent clinically, nodules and cords. Transforming growth factor beta-1 (TGF-b1) has been implicated in Dupuytren's disease development. Myofibroblasts are prevalent in nodules and may be the source of cell-mediated contraction, which combined with matrix remodelling causes tissue shortening. The hypothesis was that nodule and cord derived fibroblasts have differing contractile properties; have inherently altered tensional homeostasis and responses to mechanical stimuli. It was found that nodule cultures contained significantly greater numbers of myofibroblasts, identified using immunohistochemical staining, than cord or carpal ligament. A culture force monitor model was used to study the contractile properties of fibroblasts in culture. Mean peak force generated at 20hrs was significantly greater in nodule cells, than cord, whilst carpal ligament generated minimal force. There was a failure of force to plateau before 20hrs in Dupuytren's cells, possibly representing delayed tensional homeostasis. Responses to increased tension were investigated by subjecting gels to four uniaxial overloads. Dupuytren's cells, particularly nodule fibroblasts, exhibited an unexpected increased contractile response to the first overload. TGF-b1 stimulation caused a significant upregulation of myofibroblasts in Dupuytren's cells to 25%; it also caused an increase in contraction profiles, with elevated mean 20hr force. Greatest stimulation occurred early in contraction, 2hr gradients increasing by 250 % in nodule fibroblasts. After overloading greater contractile responses were observed in the first postoverload period and these persisted to subsequent overloads after TGF- b1 stimulation. Flexion deformities in Dupuytren's disease occur due to shortening of the affected matrix. The abnormal contractile properties and altered tensional homeostasis in resident cells that we have found may be central to this. TGF- b1 stimulation upregulated myofibroblast differentiation in Dupuytren's cells and exacerbated the abnormal contractile properties and responses to loading. Clinical relevance is discussed.

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