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Am J Physiol Lung Cell Mol Physiol (August 26, 2005). doi:10.1152/ajplung.00171.2005
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Submitted on April 15, 2005
Accepted on August 12, 2005

BMP-7 Opposes TGF {beta}1-Mediated Collagen Induction in Mouse Pulmonary Myofibroblasts through Id2

Nobuhiro Izumi1, Shinjiro Mizuguchi1, Yutaka Inagaki2, Shizuya Saika3, Norifumi Kawada4, Yuji Nakajima5, Kiyotoshi Inoue1, Shigefumi Suehiro1, Scott L Friedman6, and Kazuo Ikeda1*

1 Department of Surgery, Graduate School of Medicine, Osaka City University, Osaka, Osaka, Japan
2 Liver Fibrosis Research Unit, Tokai University School of Medicine, Isehara, Kanagawa, Japan
3 Department of Ophthalmology, Wakayama Medical University, Wakayama, Wakayama, Japan
4 Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Osaka, Japan
5 Department of Anatomy, Graduate School of Medicine, Osaka City University, Osaka, Osaka, Japan
6 Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA

* To whom correspondence should be addressed. E-mail: ikeda{at}med.osaka-cu.ac.jp.

Mesenchymal cells, primarily fibroblasts and myofibroblasts, are the principle matrix-producing cells during pulmonary fibrogenesis. TGF {beta} signaling plays an important role in stimulating the expression of type I collagen of these cells. Bone morphogenetic protein (BMP)-7, a member of the TGF{beta} superfamily, has been reported to oppose the fibrogenic activity of TGF{beta}1. Here, we have addressed the effects of BMP-7 on the fibrogenic activity of pulmonary myofibroblasts. We first established cell lines from the lungs of transgenic mice harboring the COL1A2 upstream sequence fused to luciferase. They displayed a spindle shape and expressed vimentin and {alpha} smooth muscle actin, but not E-cadherin. COL1A2 promoter activity was dose-dependently induced by TGF{beta}1, which was further augmented by adenoviral overexpression of Smad3, but was down-regulated by Smad7. Under the identical condition, adenoviral overexpression of BMP-7 attenuated the TGF{beta}1-dependent COL1A2 promoter activity. By immunocytochemistry, the ectopic expression of BMP-7 led to the nuclear localization of phospho-Smad1/5/8 and suppressed that of Smad3. BMP-7 suppressed the expression of mRNAs for COL1A2 and tissue inhibitor of metalloproteinase-2, while increasing those of inhibitors of differentiation (Id) 2 and 3. Ectopic expression of Id2 and Id3 was found to decrease the COL1A2 promoter activity. Finally, BMP-7 and Id2 decreased TGF{beta}1-dependent collagen protein secretion. In conclusion, these data demonstrate that BMP-7 antagonizes the TGF{beta}1-dependent fibrogenic activity of mouse pulmonary myofibroblastic cells by inducing Id2 and Id3.




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