A soluble transforming growth factor beta receptor expressed in muscle prevents liver fibrogenesis and dysfunction in rats.
We demonstrated that local expression of a dominant-negative type II TGF-beta receptor prevents live fibrogenesis and dysfunction in dimethylnitrosamine-treated rats. Using the same model, we have now tested whether a soluble TGF-beta receptor expressed in skeletal muscle can effectively suppress TGF-beta signaling in a remote organ (the liver). We constructed an adenovirus expressing an entire ectodomain of human TGF-beta type II receptor fused to the Fc portion of human IgG (AdTbeta-ExR). This soluble receptor secreted from AdTbeta-ExR-infected cells bound TGF-beta and blocked TGF-beta-signaling in vitro. After intramuscular injection of AdTbeta-ExR in rats, the soluble receptor protein was detectable in the blood for at least 3 weeks. When such rats were treated with dimethylnitrosamine, liver fibrosis was markedly attenuated without apparent systemic or local side effects. The hepatic hydroxyproline content was reduced to a level indistinguishable from that achieved by local expression of the dominant-negative TGF-beta receptor. Since a qualitatively and quantitatively similar suppression was achieved by the two methods, it may be concluded that the new strategy can achieve a complete inhibition of TGF-beta signaling under pathophysiological conditions in vivo. This strategy should facilitate clarification of the role of TGF-beta in vivo in various organs where direct gene transfer seems to be difficult.
Ueno
H
H
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. ueno@med.kyushu-u.ac.jp
Sakamoto
T
T
Nakamura
T
T
Qi
Z
Z
Astuchi
N
N
Takeshita
A
A
Shimizu
K
K
Ohashi
H
H
D000818:Animals; D004128:Dimethylnitrosamine / Q000633:toxicity; D015316:Genetic Therapy; D007273:Injections, Intramuscular; D008099:Liver / Q000187:drug effects / Q000503:physiopathology*; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D018482:Muscle, Skeletal / Q000378:metabolism*; D051381:Rats; D018125:Receptors, Transforming Growth Factor beta / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
D018125:Receptors, Transforming Growth Factor beta; D004128:Dimethylnitrosamine