Dysregulation of transforming growth factor beta signaling in scleroderma: overexpression of endoglin in cutaneous scleroderma fibroblasts.
OBJECTIVE
As an initial approach to understanding the basis of the systemic sclerosis (SSc; scleroderma) phenotype, we sought to identify genes in the transforming growth factor beta (TGF beta) signaling pathway that are up-regulated in lesional SSc fibroblasts relative to their normal counterparts.


METHODS
We used gene chip, differential display, fluorescence-activated cell sorter, and overexpression analyses to assess the potential role of TGF beta signaling components in fibrosis. Fibroblasts were obtained by punch biopsy from patients with diffuse cutaneous SSc of 2-14 months' duration (mean 8 months) and from age- and sex-matched healthy control subjects.


RESULTS
Unexpectedly, we found that fibroblasts from SSc patients showed elevated expression of the endothelial cell-enriched TGF beta receptor endoglin. Endoglin is a member of the nonsignaling high-affinity TGF beta receptor type III family. The expression of endoglin increased with progression of disease. Transfection of endoglin in fibroblasts suppressed the TGF beta-mediated induction of connective tissue growth factor promoter activity.


CONCLUSIONS
SSc is characterized by overproduction of matrix; that is, genes that are targets of TGF beta signaling in normal fibroblasts. Our findings suggest that lesional SSc fibroblasts may overexpress endoglin as a negative feedback mechanism in an attempt to block further induction of profibrotic genes by TGF beta.
Leask
A
A
FibroGen, Inc., South San Francisco, California 94080, USA. aleask@fibrogen.com
Abraham
D J
DJ
Finlay
D R
DR
Holmes
A
A
Pennington
D
D
Shi-Wen
X
X
Chen
Y
Y
Venstrom
K
K
Dou
X
X
Ponticos
M
M
Black
C
C
Bernabeu
C
C
Jackman
J K
JK
Findell
P R
PR
Connolly
M K
MK
D015703:Antigens, CD; D000071063:Endoglin; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D011956:Receptors, Cell Surface; D012595:Scleroderma, Systemic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; D016212:Transforming Growth Factor beta; D019010:Vascular Cell Adhesion Molecule-1