Previously published studies have demonstrated that a majority of systemic sclerosis (SSc) fibroblasts exhibit elevated levels of transforming growth factor β type I receptor (TGFβRI). An experimental model that recapitulates this condition was established in control dermal fibroblasts by titrating the dose of adenovirus vector expressing TGFβRI (AdTGFβRI). The present study was undertaken to determine the functional consequences of increased levels of TGFβRI in SSc.

Gene array analysis of control dermal fibroblasts transduced with AdTGFβRI was performed using GeneChip expression arrays. Gene validation was done by Northern blot, quantitative reverse transcriptase–polymerase chain reaction, and Western blot techniques. TGFβ blockade was performed using soluble TGFβ receptor. TGFβRI kinase/activin receptor–like kinase 5 was inhibited with pharmacologic inhibitors. TGFβRI and TGFβRII protein levels and collagen production were examined by Western blotting in primary dermal fibroblasts from 9 SSc patients and 9 healthy adults. Endogenous TGFβRI levels were suppressed in control and SSc fibroblasts using specific small interfering RNA (siRNA).

Global gene analysis indicated that a 2‐fold increase in TGFβRI levels in control fibroblasts resulted in profibrotic changes that closely resembled the phenotype of SSc fibroblasts. A total of 125 genes were up‐regulated, including COL1A1, COL1A2, and connective tissue growth factor, and 206 genes were down‐regulated. Elevated production of collagen in cells transduced with AdTGFβRI was dependent on the autocrine TGFβ, but not TGFβRI kinase activity. Eight of the 9 SSc strains exhibited increased levels of TGFβRI protein, which correlated with increased collagen synthesis. Treatment of SSc and matched control fibroblasts with siRNA that normalizes TGFβRI levels reverted collagen protein production in SSc fibroblasts to the levels observed in control fibroblasts.

Our findings demonstrate that aberrantly expressed TGFβRI may drive an autocrine loop involved in the up‐regulation of collagen and other matrix‐related genes in SSc fibroblasts.