Transforming Growth Factor-β1 Stimulation Enhances Dupuytren's Fibroblast Contraction in Response to Uniaxial Mechanical Load Within a 3-Dimensional Collagen Gel

Abstract

A function of fibroblasts is the generation of cytomechanical force within their surrounding extracellular matrix. Abnormalities in force generation may be the cause of many pathologic conditions including scarring, and some fibroproliferative disorders such as Dupuytren's disease, which is the focus of this report. This work investigated the cytomechanical responses of Dupuytren's-derived fibroblasts to externally applied mechanical force using a culture force monitor model, with and without stimulation with the fibrosis-linked cytokine, transforming growth factor-beta1 (TGF-beta1). We compared these responses with cytomechanical responses of fibroblasts derived from the transverse carpal ligament. Dupuytren's fibroblasts display a significantly greater ability to contract a collagen matrix compared with control fibroblasts, with a maximum generated force of 131 dynes (p < .001). These cells did not exhibit a characteristic plateau phase in the contraction, which indicates a delay in achieving tensional homeostasis from Dupuytren's-derived cells. After being subjected to uniaxial overload and underload, Dupuytren's fibroblasts responded by increased force generation, whereas control fibroblasts responded by a reduction in force in response to an overload, and contraction in response to an underload. These changes were exacerbated by the addition of the profibrotic factor TGF-beta1, with a significant increase in generated force for all cell types, in particular during the early phase of fibroblast attachment and contraction, and a positive contraction gradient in response to overloading forces. These data suggest that cells derived from this fibrotic disease display characteristic abnormalities in force generation profiles. Their default response to loading or underloading is contraction, or increased force generation. This work highlights the role of TGF-beta1 as a mechano-transduction cytokine, which has an influence on the early phase cell of force generation, as well as a role in mechanical responses of cells to external mechanical stimuli. This, in turn, may influence the progression of Dupuytren's disease and the high rates of recurrence seen postoperatively.