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Inhibition of Cell Migration in Dupuytren's -derived Fibroblasts by Activation of Cyclic AMP (cAMP)
Latha Satish, MSc, PhD; Fang Liu, MD; Phillip Gallo, PhD; Mark Baratz, MD; Sandeep Kathju, MD, PhD
University of Pittsburgh, Pittsburgh, PA

Hypothesis: We hypothesized that increased activation of cyclic AMP (cAMP) pathways would reduce both basal and PDGF-induced cell migration of Dupuytren’s contracture-derived fibroblasts.
Method: Fibroblasts harvested from actively diseased Dupuytren’s contracture cord (DC) and from the adjacent grossly unaffected palmar fascia in the same patients (PF) were compared to fibroblasts derived from the palmar fascia of carpal tunnel (CT) patients. Cells treated with or without PDGF (2ng/ml) and/or forskolin (10 µM, a known cAMP inducer) were subjected to an in-vitro wound healing “scratch” assay to measure cell motility into the denuded zone; photographs were taken at 0h and 48h and quantified.
Results: We found higher basal motility in DC- compared to unaffected palmar fascia (PF-) and CT-derived fibroblasts. PDGF stimulated cell motility in all three populations, and the addition of forskolin inhibited both basal and PDGF-induced cell migration in all three cell types. Interestingly, the inhibitory effect of forskolin on PDGF-induced cell migration was more pronounced in DC-derived fibroblasts compared to the other two cell types. Western blot analysis showed that neither PDGF nor forskolin exposure had any effect on phosphorylation of p38 and PI3 kinase in DC-derived fibroblasts. Both forskolin and PDGF increased p42/44 MAP kinase phosphorylation. In contrast, elevated cAMP resulted in increased RhoA phosphorylation and a subsequent decrease in the level of activated RhoA in DC-derived fibroblasts.
Conclusions: These results for the first time examine the effects of PDGF and cAMP on DC fibroblast motility and show that elevated cAMP can inhibit the actions of PDGF, possibly through a RhoA intermediary. Since fibroblast motility is one element that contributes to the tissue deforming forces that can result in clinical contracture, these results suggest that increasing cAMP in DC cells may be a means of forestalling clinical disease progression or recurrence.


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