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1-Mediated Collagen Induction in Mouse Pulmonary Myofibroblasts through Id2
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 
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 superfamily, has been reported to oppose the fibrogenic activity of TGF1. 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 
smooth muscle actin, but not E-cadherin. COL1A2 promoter activity was dose-dependently induced by TGF1, 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 TGF1-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 TGF1-dependent collagen protein secretion. In conclusion, these data demonstrate that BMP-7 antagonizes the TGF1-dependent fibrogenic activity of mouse pulmonary myofibroblastic cells by inducing Id2 and Id3.
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