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Disruption of LTBP-4 function reduces TGF-beta activation and enhances BMP-4 signaling in the lung
Katri Koli1, Frank Wempe, Anja Sterner-Kock
1Department 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.
Insights
Loss of latent transforming growth factor-beta (TGF-beta) binding protein-4 (LTBP-4) impairs TGF-beta activation, leading to abnormal lung development and increased bone morphogenic protein-4 signaling.
Area of Science:
- Cell Biology
- Developmental Biology
- Cancer Biology
Background:
- Latent TGF-beta binding protein (LTBP)-4 is crucial for normal lung development and colorectal cancer suppression.
- LTBP-4 deficiency results in impaired TGF-beta activation and altered TGF-beta isoform expression.
Purpose of the Study:
- To investigate the role of LTBP-4 in TGF-beta activation and its downstream effects on lung development and cancer.
- To elucidate the molecular mechanisms linking LTBP-4 deficiency to altered signaling pathways.
Main Methods:
- Utilized LTBP-4 knockout (LTBP-4 -/-) mice to study lung fibroblast function.
- Performed gene expression analysis (microarrays) to identify altered signaling pathways.
- Investigated the rescue effects of LTBP-4 transfection and active TGF-beta1 treatment.
Main Results:
- LTBP-4 -/- fibroblasts showed decreased active TGF-beta and increased latent TGF-beta secretion, particularly TGF-beta2 and -beta3.
- Elevated bone morphogenic protein (BMP)-4 expression and reduced gremlin levels were observed in LTBP-4 -/- lungs.
- BMP-4 target genes and fibronectin deposition were increased, indicating enhanced BMP-4 signaling.
- LTBP-4 reintroduction rescued the fibroblast phenotype, while LTBP-1 was ineffective.
Conclusions:
- LTBP-4 is essential for the proper activation of TGF-beta1.
- The absence of LTBP-4 leads to dysregulated TGF-beta signaling and enhanced BMP-4 pathway activity.
- These molecular changes contribute to abnormal lung development and cancer predisposition observed in LTBP-4 deficient mice.
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