BMP-7 opposes TGF-β1-mediated collagen induction in mouse pulmonary myofibroblasts through Id2

Nobuhiro Izumi, Shinjiro Mizuguchi, Yutaka Inagaki, Shizuya Saika, Norifumi Kawada, Yuji Nakajima, Kiyotoshi Inoue, Shigefumi Suehiro, Scott L. Friedman, Kazuo Ikeda

Research output: Contribution to journalArticlepeer-review

100 Scopus citations


Mesenchymal cells, primarily fibroblasts and myofibroblasts, are the principal matrix-producing cells during pulmonary fibrogenesis. Transforming growth factor (TGF)-β 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-β superfamily, has been reported to oppose the fibrogenic activity of TGF-β1. 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 α-smooth muscle actin, but not E-cadherin. COL1A2 promoter activity was dose dependently induced by TGF-β1, which was further augmented by adenoviral overexpression of Smad3, but was downregulated by Smad7. Under the identical condition, adenoviral overexpression of BMP-7 attenuated the TGF-β1-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-β1-dependent collagen protein secretion. In conclusion, these data demonstrate that BMP-7 antagonizes the TGF-β1-dependent fibrogenic activity of mouse pulmonary myofibroblastic cells by inducing Id2 and Id3.

Original languageEnglish
Pages (from-to)L120-L126
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Issue number1
StatePublished - Jan 2006


  • Bone morphogenetic protein
  • Inhibitors of differentiation
  • Transforming growth factor


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