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

Koli K, Wempe F, Sterner-Kock A, Kantola A, Komor M, Hofmann WK, von Melchner H, Keski-Oja J - J. Cell Biol. (2004)

Bottom Line: These results suggested that TGF-beta 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.Treatment with active TGF-beta1 rescued BMP-4 and gremlin expression to wild-type levels.

View Article: PubMed Central - PubMed

Affiliation: Department of Virology, Haartman Institute and Helsinki University Hospital, University of Helsinki, 00014 Helsinki, Finland. katri.koli@helsinki.fi

ABSTRACT
Disruption of latent TGF-beta 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-beta, whereas secretion of latent TGF-beta was significantly increased. Expression and secretion of TGF-beta2 and -beta3 increased considerably. These results suggested that TGF-beta 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-beta1 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-beta1 leads to enhanced BMP-4 signaling in mouse lung.

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Decreased levels of gremlin and increased levels of BMP-4 and phosphorylated Smad1 in −/− lung tissue. Lung sections from wt (+/+) and LTBP-4 −/− mice were stained for BMP-4, gremlin, phosphorylated Smad1, and total Smad1. Positive staining is reddish-brown.
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fig6: Decreased levels of gremlin and increased levels of BMP-4 and phosphorylated Smad1 in −/− lung tissue. Lung sections from wt (+/+) and LTBP-4 −/− mice were stained for BMP-4, gremlin, phosphorylated Smad1, and total Smad1. Positive staining is reddish-brown.

Mentions: To analyze whether or not BMP-4–mediated signals were elevated in vivo, lung tissues were stained with antibodies against BMP-4 and gremlin. A clear increase in BMP-4 staining was observed in parallel with loss of expression of gremlin in −/− lung tissues (Fig. 6). This was accompanied by increased signaling, as shown by intense staining for the BMP-specific signaling molecule, phosphorylated Smad1 (Fig. 6). The total levels of unphosphorylated Smad1 protein in −/− and wt lungs were comparable.


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

Koli K, Wempe F, Sterner-Kock A, Kantola A, Komor M, Hofmann WK, von Melchner H, Keski-Oja J - J. Cell Biol. (2004)

Decreased levels of gremlin and increased levels of BMP-4 and phosphorylated Smad1 in −/− lung tissue. Lung sections from wt (+/+) and LTBP-4 −/− mice were stained for BMP-4, gremlin, phosphorylated Smad1, and total Smad1. Positive staining is reddish-brown.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172518&req=5

fig6: Decreased levels of gremlin and increased levels of BMP-4 and phosphorylated Smad1 in −/− lung tissue. Lung sections from wt (+/+) and LTBP-4 −/− mice were stained for BMP-4, gremlin, phosphorylated Smad1, and total Smad1. Positive staining is reddish-brown.
Mentions: To analyze whether or not BMP-4–mediated signals were elevated in vivo, lung tissues were stained with antibodies against BMP-4 and gremlin. A clear increase in BMP-4 staining was observed in parallel with loss of expression of gremlin in −/− lung tissues (Fig. 6). This was accompanied by increased signaling, as shown by intense staining for the BMP-specific signaling molecule, phosphorylated Smad1 (Fig. 6). The total levels of unphosphorylated Smad1 protein in −/− and wt lungs were comparable.

Bottom Line: These results suggested that TGF-beta 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.Treatment with active TGF-beta1 rescued BMP-4 and gremlin expression to wild-type levels.

View Article: PubMed Central - PubMed

Affiliation: Department of Virology, Haartman Institute and Helsinki University Hospital, University of Helsinki, 00014 Helsinki, Finland. katri.koli@helsinki.fi

ABSTRACT
Disruption of latent TGF-beta 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-beta, whereas secretion of latent TGF-beta was significantly increased. Expression and secretion of TGF-beta2 and -beta3 increased considerably. These results suggested that TGF-beta 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-beta1 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-beta1 leads to enhanced BMP-4 signaling in mouse lung.

Show MeSH
Related in: MedlinePlus