Aberrant transforming growth factor β (TGFβ) signaling has been implicated in the pathogenesis of scleroderma (systemic sclerosis [SSc]), but the contribution of specific components in this pathway to SSc fibroblast phenotype remains unclear. This study was undertaken to delineate the role of TGFβ receptor type I (TGFβRI) and TGFβRII in collagen overexpression by SSc fibroblasts.


Primary dermal fibroblasts from SSc patients and healthy adults were studied (n = 10 matched pairs). Adenoviral vectors were generated for TGFβRI (AdTGFβRI), TGFβRII (AdTGFβRII), and kinase-deficient TGFβRII (AdΔkRII). TGFβRI basal protein levels were analyzed by 35S-methionine labeling/immunoprecipitation and immunohistochemistry. Type I collagen and TGFβRII basal protein levels were analyzed by Western blot and newly secreted collagen by 3H-proline incorporation assay.


Analysis of endogenous TGFβRI and TGFβRII protein levels revealed that SSc TGFβRI levels were increased 1.7-fold (P = 0.008; n = 7) compared with levels in healthy controls, while TGFβRII levels were decreased by 30% (P = 0.03; n = 7). This increased TGFβRI:TGFβRII ratio correlated with SSc collagen overexpression. To determine the consequences of altered TGFβRI:TGFβRII ratio on collagen expression, healthy fibroblasts were transduced with AdTGFβRI or AdTGFβRII. Forced expression of TGFβRI in the range corresponding to elevated SSc TGFβRI levels increased basal collagen expression in a dose-dependent manner, while similar TGFβRII overexpression had no effect, although transduction of fibroblasts at higher multiplicities of infection led to a marked reduction of basal collagen levels. Blockade of TGFβ signaling via AdΔkRII resulted in ∼50% inhibition of basal collagen levels in healthy fibroblasts and in 5 of 9 SSc cell lines. A subset of SSc fibroblasts (4 of 9 cell lines) was resistant to this treatment. SSc fibroblasts with the highest levels of TGFβRI were the least responsive to collagen inhibition via ΔkRII.


This study indicates that an increased TGFβRI:TGFβRII ratio may underlie aberrant TGFβ signaling in SSc and contribute to elevated basal collagen production, which is insensitive to TGFβ signaling blockade via ΔkRII.