INCREASED EXPRESSION OF TGF-BETA RECEPTORS BY SCLERODERMA FIBROBLASTS- EVIDENCE FOR CONTRIBUTION OF AUTOCRINE TGF-BETA SIGNALING TO SCLERODERMA PHENOTYPE

Scleroderma fibroblasts exhibit numerous phenotypic differences when c ompared with healthy skin fibroblasts. Some of these differences, in p articular overexpression of collagen type I and other extracellular ma trix proteins, parallel the effect of transforming growth factor-beta (TGF-beta) on dermal fibroblasts, suggesting that the scleroderma fibr oblast phenotype may result from activation of autocrine TGF-beta sign aling. To test this hypothesis we examined the role of TGF-beta Type I and Type II receptors in regulating collagen type I transcription, We have shown that overexpression of either Type I or Type II receptors significantly (3-4-fold) increases alpha 2 (I) collagen promoter activ ity in transient transfection assays in dermal fibroblasts. Addition o f anti-TGF-beta antibody abolished, whereas addition of plasmin enhanc ed, the stimulatory effect of receptor overexpression on collagen prom oter activity, suggesting that this effect depends on autocrine TGF-be ta, Moreover, these cotransfection experiments indicated that expressi on levels of TGF-beta receptors is a limiting factor in the autocrine regulation of collagen type I transcription by TGF-beta. Comparison of the TGF-beta receptor Type I and Type II mRA expression levels in scl eroderma and normal fibroblasts have indicated elevated expression (2- fold) of both receptor types in scleroderma cells, which correlated wi th increased binding of TGF-beta. Significantly, elevated TGF-beta rec eptor levels correlated with elevated alpha 2 (I) collagen mRNA levels . These results suggest that the elevated production of collagen type I by scleroderma fibroblasts results from overexpression of TGF-beta r eceptors.