Adenovirus-mediated expression of BMP-7 suppresses the development of liver fibrosis in rats.
BACKGROUND
Liver cirrhosis, which is caused by the accumulation of extracellular matrix materials, is a serious clinical problem that can progress to hepatic failure. Transforming growth factor-beta (TGFbeta) plays a pivotal role in extracellular matrix production, but bone morphogenetic protein (BMP)-7, a member of the TGFbeta superfamily, can antagonise the fibrogenic activity of TGFbeta.


OBJECTIVE
In this study, we examined whether adenovirus-mediated overexpression of BMP-7 (Ad-BMP-7) antagonised the effect of TGFbeta in vitro and in vivo.


RESULTS
In primary cultured rat stellate cells and the LX-2 human stellate cell line, induction of BMP-7 by Ad-BMP-7 infection decreased the expression of collagen 1A2 mRNA and smooth muscle alpha-actin in the presence or absence of TGFbeta, via Smad 1/5/8 phosphorylation. BMP-7 triggered the mRNA expression of inhibitors of differentiation 2 (Id2) in LX-2. Although endogenous expression of BMP-7 was hardly detectable, Smad1 and Id2 overexpression increased BMP-7 expression in LX-2. A liver fibrosis model was induced by the repetitive intraperitoneal injection of thioacetamide (200 mg/kg body weight) twice per week for up to 7 weeks. In rats administered Ad-BMP-7 via the tail vein, hydroxyproline content and the areas stained by Sirius red dye in the liver were significantly reduced compared to controls. Ad-Id2 also reduced fibrosis.


CONCLUSIONS
These data demonstrate that BMP-7, Smad 1/5/8 and Ids interact to antagonise hepatic fibrogenesis.
Kinoshita
Kohji
K
First Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan.
Iimuro
Yuji
Y
Otogawa
Kohji
K
Saika
Shizuya
S
Inagaki
Yutaka
Y
Nakajima
Yuji
Y
Kawada
Norifumi
N
Fujimoto
Jiro
J
Friedman
Scott L
SL
Ikeda
Kazuo
K
D000199:Actins / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D002352:Carrier Proteins / Q000502:physiology; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2 / Q000378:metabolism; D008103:Liver Cirrhosis / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013853:Thioacetamide; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*
D000199:Actins; D051017:Apoptosis Regulatory Proteins; C525819:BMP7 protein, human; C525821:Bmp7 protein, rat; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D024042:Collagen Type I; C489013:DIABLO protein, rat; C497450:ID2 protein, human; D051797:Inhibitor of Differentiation Protein 2; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D013853:Thioacetamide