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This Article Full Text Full Text (PDF) All Versions of this Article: 290/1/L120    most recent 00171.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (15) Citing Articles via Google Scholar Google Scholar Articles by Izumi, N. Articles by Ikeda, K. Search for Related Content PubMed PubMed Citation Articles by Izumi, N. Articles by Ikeda, K.

BMP-7 opposes TGF-1-mediated collagen induction in mouse pulmonary myofibroblasts through Id2

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

Submitted 15 April 2005 ; accepted in final form 12 August 2005

Mesenchymal cells, primarily fibroblasts and myofibroblasts, are the principal matrix-producing cells during pulmonary fibrogenesis. Transforming growth factor (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 TGF-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 -smooth muscle actin, but not E-cadherin. COL1A2 promoter activity was dose dependently induced by TGF-1, 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-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-1-dependent collagen protein secretion. In conclusion, these data demonstrate that BMP-7 antagonizes the TGF-1-dependent fibrogenic activity of mouse pulmonary myofibroblastic cells by inducing Id2 and Id3.

bone morphogenetic protein; transforming growth factor; inhibitors of differentiation

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