title: Increased expression of TGF-beta receptors by scleroderma fibroblasts: evidence for contribution of autocrine TGF-beta signaling to scleroderma phenotype.
abstract: Scleroderma fibroblasts exhibit numerous phenotypic differences when compared with healthy skin fibroblasts. Some of these differences, in particular overexpression of collagen type I and other extracellular matrix proteins, parallel the effect of transforming growth factor-beta (TGF-beta) on dermal fibroblasts, suggesting that the scleroderma fibroblast phenotype may result from activation of autocrine TGF-beta signaling. 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 alpha2 (I) collagen promoter activity in transient transfection assays in dermal fibroblasts. Addition of anti-TGF-beta antibody abolished, whereas addition of plasmin enhanced, the stimulatory effect of receptor overexpression on collagen promoter activity, suggesting that this effect depends on autocrine TGF-beta. Moreover, these cotransfection experiments indicated that expression 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 scleroderma and normal fibroblasts have indicated elevated expression (2-fold) of both receptor types in scleroderma cells, which correlated with increased binding of TGF-beta. Significantly, elevated TGF-beta receptor levels correlated with elevated alpha2 (I) collagen mRNA levels. These results suggest that the elevated production of collagen type I by scleroderma fibroblasts results from overexpression of TGF-beta receptors.
authors.affiliation: Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston 29425-2229, USA.
authors.forename: T
authors.initials: T
authors.lastname: Kawakami
authors.forename: H
authors.initials: H
authors.lastname: Ihn
authors.forename: W
authors.initials: W
authors.lastname: Xu
authors.forename: E
authors.initials: E
authors.lastname: Smith
authors.forename: C
authors.initials: C
authors.lastname: LeRoy
authors.forename: M
authors.initials: M
authors.lastname: Trojanowska
mesh_terms: D003094:Collagen / Q000096:biosynthesis / Q000235:genetics; D005347:Fibroblasts / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D010641:Phenotype; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis* / Q000502:physiology; D012595:Scleroderma, Systemic / Q000235:genetics / Q000473:pathology*; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D003094:Collagen