Dermal fibroblasts from venous ulcers are unresponsive to the action of transforming growth factor-beta 1

Failure to reepithelialize is the major clinical problem in venous ulcers. It is not clear whether the problem resides with keratinocytes or with inadequate and improper formation of extracellular matrix. In this study, we characterized the biosynthetic activity and response to transforming growth factor-beta 1 (TGF-beta) of dermal fibroblast cultures isolated from biopsies of venous ulcers and from normal thigh skin (controls) of seven patients. We found that baseline 3H-proline incorporation was similar in fibroblasts from venous ulcers and control skin (p= 0.1716). No difference was detected by ELISA between ulcer and control fibroblasts in the synthesis of total TGF-beta (p = 0.2309), and the mRNA levels for alpha 1(I) procollagen and TGF-beta were comparable in both groups. However, TGF-beta (0.1-5 ng/ml) enhanced collagen protein synthesis by more than 60% and in a dose-dependent manner (r = 0.997) in control fibroblast cultures, while failing to stimulate collagen production by venous ulcer fibroblasts (p = 0.0001). This unresponsiveness to TGF-beta was associated with up to a fourfold decrease in TGF-beta Type II receptors. We conclude that fibroblasts from the edge of non-healing venous ulcers are unresponsive to the action of TGF-beta, and that this blunted response may cause faulty deposition of the extracellular matrix needed for reepithelialization and wound healing.