Feedback inhibition of high TGF-β1 concentrations on myofibroblast induction and contraction by Dupuytren's fibroblasts

Myofibroblasts and TGF-β1 are implicated in Dupuytren's contracture. Transforming growth fact- or β1(TGF-β1) (1-10 ng/ml) increases myofibroblast induction in Dupuytren's fibroblasts and contraction in a collagen model. However, higher doses (20-30 ng/ml) inhibit contraction in dermal fibroblasts. We hypothesized higher doses of TGF-β1 would inhibit induction of myofibroblasts and contraction by Dupuytren's fibroblasts. Increasing doses of TGF-β1 (0-30 ng/ml) were tested on Dupuytren's fibroblasts using immunofluorescence to determine myofibroblast upregulation and a 3D collagen model used to determine contractile forces. Flexor retinaculum fibroblasts were used as controls. TGF-β1 induced myofibroblasts in Dupuytren's fibroblasts (n=3) from 12% (0 ng/ml) to 23% (12.5 ng/ml) at 24 hours but dropped to 13% at 30 ng/ml (P<0.05). This response was mirrored in the contraction profiles. These trends were similar for flexor retinaculum fibroblasts (n=3), but contractile forces and myofibroblast induction were significantly less (P<0.001). This is the first report of negative feedback inhibition of TGF-β1 at higher concentrations in Dupuytren's fibroblasts.