SB-431542 inhibits TGF-beta-induced contraction of collagen gel by normal and keloid fibroblasts.
BACKGROUND
Transforming growth factor (TGF)-beta induces fibroblast contraction, which is implicated in wound healing and keloid formation. SB-431542 is a novel specific inhibitor of TGF-beta type I receptor kinase activity.


OBJECTIVE
We sought to determine whether SB-431542 inhibited TGF-beta-induced fibroblast contraction.


METHODS
We used an in vitro type I collagen gel contraction assay with normal or keloid dermal fibroblasts incorporated.


RESULTS
TGF-beta induced contraction of collagen gels with normal dermal fibroblasts incorporated, which was efficiently suppressed by SB-431542. Keloid fibroblasts showed higher basal contraction of collagen gels in the absence of TGF-beta than normal fibroblasts, which was enhanced by addition of TGF-beta. SB-431542 suppressed both the basal and TGF-beta-enhanced contraction of collagen gels by keloid fibroblasts. These inhibitory effects of SB-431542 were associated with suppression of TGF-beta-induced alpha-smooth muscle actin (alpha-SMA) expression and phosphorylation of Smad2 in normal and keloid fibroblasts.


CONCLUSIONS
SB-431542 can suppress TGF-beta-induced contraction of collagen gel by normal and keloid dermal fibroblasts. Importantly, SB-431542 can inhibit basal contraction of collagen gel by keloid fibroblasts. These results suggest that an inhibitor of TGF-beta type I receptor kinase activity may have therapeutic potential for excessive skin contraction as observed in keloid.
Hasegawa
Toshio
T
Department of Dermatology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
Nakao
Atsuhito
A
Sumiyoshi
Koji
K
Tsuchihashi
Hitoshi
H
Ogawa
Hideoki
H
D000199:Actins / Q000032:analysis; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D003094:Collagen / Q000502:physiology*; D004149:Dioxoles / Q000494:pharmacology* / Q000627:therapeutic use; D005347:Fibroblasts / Q000502:physiology; D005782:Gels; D006801:Humans; D007627:Keloid / Q000188:drug therapy*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D000199:Actins; D001549:Benzamides; D004149:Dioxoles; D005782:Gels; D016212:Transforming Growth Factor beta; D003094:Collagen