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Published online 4 October 2004. doi:10.1083/jcb.200403067
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 167, Number 1, 123-133
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Article

 Disruption of LTBP-4 function reduces TGF-ß activation and enhances BMP-4 signaling in the lung

Katri Koli1,2, Frank Wempe3, Anja Sterner-Kock3,4, Anna Kantola1,2, Martina Komor5, Wolf-K. Hofmann5, Harald von Melchner3, and Jorma Keski-Oja1,2

1 Department of Virology, Haartman Institute and Helsinki University Hospital, University of Helsinki, 00014 Helsinki, Finland
2 Department of Pathology, Haartman Institute and Helsinki University Hospital, University of Helsinki, 00014 Helsinki, Finland
3 Laboratory for Molecular Hematology, University of Frankfurt Medical School, 60596 Frankfurt am Main, Germany
4 Institute of Veterinary Pathology, Freie University, 14163 Berlin, Germany
5 Department of Hematology/Oncology, University Hospital, 60596 Frankfurt am Main, Germany

Correspondence to Katri Koli: katri.koli{at}helsinki.fi

Disruption of latent TGF-ß binding protein (LTBP)–4 expression in the mouse leads to abnormal lung development and colorectal cancer. Lung fibroblasts from these mice produced decreased amounts of active TGF-ß, whereas secretion of latent TGF-ß was significantly increased. Expression and secretion of TGF-ß2 and -ß3 increased considerably. These results suggested that TGF-ß activation but not secretion would be severely impaired in LTBP-4 –/– fibroblasts. Microarrays revealed increased expression of bone morphogenic protein (BMP)–4 and decreased expression of its inhibitor gremlin. This finding was accompanied by enhanced expression of BMP-4 target genes, inhibitors of differentiation 1 and 2, and increased deposition of fibronectin-rich extracellular matrix. Accordingly, increased expression of BMP-4 and decreased expression of gremlin were observed in mouse lung. Transfection of LTBP-4 rescued the –/– fibroblast phenotype, while LTBP-1 was inefficient. Treatment with active TGF-ß1 rescued BMP-4 and gremlin expression to wild-type levels. Our results indicate that the lack of LTBP-4–mediated targeting and activation of TGF-ß1 leads to enhanced BMP-4 signaling in mouse lung.

Abbreviations used in this paper: BMP, bone morphogenic protein; CTGF, connective tissue growth factor; GADPH, glyceraldehyde-3-phosphate dehydrogenase; Id, inhibitor of differentiation; LTBP, latent TGF-ß binding protein; MMP, matrix metalloproteinase; PAI-1, plasminogen activator inhibitor-1; wt, wild-type.


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