Differential expression of transforming growth factor-beta receptors I andII and activation of Smad 3 in keloid fibroblasts

Keloids represent a dysregulated response to cutaneous wounding that result s in an excessive deposition of extracellular matrix, especially collagen. However, the molecular mechanisms regulating this pathologic collagen depos ition still remain to be elucidated. A previous study by this group demonst rated that transforming growth factor (TGF)-beta1 and -beta2 ligands were e xpressed at greater levels in keloid fibroblasts when compared with normal human dermal fibroblasts (NHDFs), suggesting that TGF-beta may play a fibro sis-promoting role in keloid pathogenesis. To explore the biomolecular mechanisms of TGF-beta in keloid formation, the authors first compared the expression levels of the type I and type II TGF -beta receptors in keloid fibroblasts and NHDFs. Next, they investigated th e phosphorylation of Smad 3, an intracellular TGF-beta signaling molecule, in keloid fibroblasts and NHDFs. Finally, they examined the regulation of T GF-beta receptor II by TGF-beta1, TGF-beta2, and TGF-beta3 ligands. Our findings demonstrated an increased expression of TGF-beta receptors (ty pes I and II) and increased phosphorylation of Smad 3 in keloid fibroblasts relative to NHDFs. These data support a possible role of TGF-beta and its receptors as fibrosis-inducing growth factors in keloids. In addition, all three isoforms of recombinant human TGF-beta proteins could further stimula te the expression of TGF-beta receptor II in both keloids and NHDFs. Taken together, these results substantiate the hypothesis that the elevated level s of TGF-beta ligands and receptors present in keloids may support increase d signaling and a potential role for TGF-beta in keloid pathogenesis.