International Journal of Scientific Engineering and Technology

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Signaling Cross-Talk Between Transforming Growth Factor-Beta (TGF-β) and Bone Morphogenic Protein (BMP) Pathways in Human Endometrial and Endometriotic Cells


Affiliations
1 Center of Gynecology and Obstetrics, Justus Liebig University, Giessen, Germany
2 Department of Biochemistry, University of Nairobi, Nairobi, Kenya
 

Transforming growth factor-beta (TGF-β) and bone morphogenic protein (BMP) signaling pathways are involved in the vast majority of cellular processes and are fundamentally important during the entire life of all metazoans. TGF-βs and BMPs transduce their signals via canonical Smad-dependent pathways which involve TGF-β/BMP ligands, receptors and Smad molecules. Also, non-canonical Smad-independent signalling pathways are involved in TGF-β/BMP signal transduction. Here we investigated signalling cross-talk between the pathways downstream of TGF-β and BMP signalling in endometrial and endometriotic cells. Treatment of endometrial and endometriotic stromal and epithelial cells with TGF-β1 or TGF-β2 increased secretion of plasminogen activator inhibitor 1 (PAI-1) dramatically in all cell lines. Of note, higher PAI-1 secretion was observed in endometriotic cells compared to endometrial cells. Both a transforming growth factor-beta receptor-1 (TβRI) and a Bone morphogenic protein receptor1 (BMPR1) inhibitors completely blocked the TGF-β-induced PAI-1 secretion in all cell lines while a specific inhibitor of Smad3 (SiS3) had a partial effect on PAI-1 secretion in all cell lines. Additionally, we showed that Activin Receptor-Like kinase (ALK-2) is the main BMP receptor that is responsible for complete blockage of TGF-β-induced PAI-1 secretion whereas, ALK-3 and ALK-6 exhibited partial effects on PAI-1 secretion. In summary, the complete inhibition of TGF-β-induced PAI-1 secretion by a general BMPR1 and ALK-2 inhibitors suggest a possible cross-talk between TGF-β and BMP pathways. Since only ALK-2 had a complete decrease of TGF-β-induced PAI-1 secretion compared to ALK-3 and ALK-6 in all cells, then our results demonstrate the importance of ALK-2 as a point of cross-talk of TGF-β and BMP pathways. Furthermore, we showed TGF-β-induced phosphorylation of Smad1 in all cells upon TGF-beta treatment. Our result further confirms that the Smads are the most important intracellular transducers of TGF-β and BMP signals.

Keywords

Endometriosis, Transforming Growth Factorbetas, Bone Morphogenic Protein, Activin Receptor-Like Kinase.
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  • Signaling Cross-Talk Between Transforming Growth Factor-Beta (TGF-β) and Bone Morphogenic Protein (BMP) Pathways in Human Endometrial and Endometriotic Cells

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Authors

Ezekiel O. Mecha
Center of Gynecology and Obstetrics, Justus Liebig University, Giessen, Germany
Cong Sui
Center of Gynecology and Obstetrics, Justus Liebig University, Giessen, Germany
Charles O. A. Omwandho
Department of Biochemistry, University of Nairobi, Nairobi, Kenya
Hans-Rudolf Tinneberg
Center of Gynecology and Obstetrics, Justus Liebig University, Giessen, Germany
Lutz Konrad
Center of Gynecology and Obstetrics, Justus Liebig University, Giessen, Germany

Abstract


Transforming growth factor-beta (TGF-β) and bone morphogenic protein (BMP) signaling pathways are involved in the vast majority of cellular processes and are fundamentally important during the entire life of all metazoans. TGF-βs and BMPs transduce their signals via canonical Smad-dependent pathways which involve TGF-β/BMP ligands, receptors and Smad molecules. Also, non-canonical Smad-independent signalling pathways are involved in TGF-β/BMP signal transduction. Here we investigated signalling cross-talk between the pathways downstream of TGF-β and BMP signalling in endometrial and endometriotic cells. Treatment of endometrial and endometriotic stromal and epithelial cells with TGF-β1 or TGF-β2 increased secretion of plasminogen activator inhibitor 1 (PAI-1) dramatically in all cell lines. Of note, higher PAI-1 secretion was observed in endometriotic cells compared to endometrial cells. Both a transforming growth factor-beta receptor-1 (TβRI) and a Bone morphogenic protein receptor1 (BMPR1) inhibitors completely blocked the TGF-β-induced PAI-1 secretion in all cell lines while a specific inhibitor of Smad3 (SiS3) had a partial effect on PAI-1 secretion in all cell lines. Additionally, we showed that Activin Receptor-Like kinase (ALK-2) is the main BMP receptor that is responsible for complete blockage of TGF-β-induced PAI-1 secretion whereas, ALK-3 and ALK-6 exhibited partial effects on PAI-1 secretion. In summary, the complete inhibition of TGF-β-induced PAI-1 secretion by a general BMPR1 and ALK-2 inhibitors suggest a possible cross-talk between TGF-β and BMP pathways. Since only ALK-2 had a complete decrease of TGF-β-induced PAI-1 secretion compared to ALK-3 and ALK-6 in all cells, then our results demonstrate the importance of ALK-2 as a point of cross-talk of TGF-β and BMP pathways. Furthermore, we showed TGF-β-induced phosphorylation of Smad1 in all cells upon TGF-beta treatment. Our result further confirms that the Smads are the most important intracellular transducers of TGF-β and BMP signals.

Keywords


Endometriosis, Transforming Growth Factorbetas, Bone Morphogenic Protein, Activin Receptor-Like Kinase.