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BMP-2 and TGF?2 shared pathways regulate endocardial cell transformation.

ABSTRACT: Valvular heart disease is a major cause of mortality and morbidity. Revealing the cellular processes and molecules that regulate valve formation and remodeling is required to develop effective therapies. A key step in valve formation during heart development is the epithelial-mesenchymal transformation (EMT) of a subpopulation of endocardial cells in the atrioventricular cushion (AVC). The type III transforming growth factor-? receptor (TGF?R3) regulates AVC endocardial cell EMT in vitro and mesenchymal cell differentiation in vivo. Little is known concerning the signaling mechanisms downstream of TGF?R3. Here we use endocardial cell EMT in vitro to determine the role of 2 well-characterized downstream TGF? signaling pathways in TGF?R3-dependent endocardial cell EMT. Targeting of Smad4, the common mediator Smad, demonstrated that Smad signaling is required for EMT in the AVC and TGF?R3-dependent EMT stimulated by TGF?2 or BMP-2. Although we show that Smads 1, 2, 3, and 5 are required for AVC EMT, overexpression of Smad1 or Smad3 is not sufficient to induce EMT. Consistent with the activation of the Par6/Smurf1 pathway downstream of TGF?R3, targeting ALK5, Par6, or Smurf1 significantly inhibited EMT in response to either TGF?2 or BMP-2. The requirement for ALK5 activity, Par6, and Smurf1 for TGF?R3-dependent endocardial cell EMT is consistent with the documented role of this pathway in the dissolution of tight junctions. Taken together, our data demonstrate that TGF?R3-dependent endocardial cell EMT stimulated by either TGF?2 or BMP-2 requires Smad4 and the activation of the Par6/Smurf1 pathway.

SUBMITTER: Townsend TA

PROVIDER: S-EPMC3128155 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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BMP-2 and TGFβ2 shared pathways regulate endocardial cell transformation.

Townsend Todd A TA Robinson Jamille Y JY Deig Christopher R CR Hill Cynthia R CR Misfeldt Andrew A Blobe Gerard C GC Barnett Joey V JV

Cells, tissues, organs 20110107 1

Valvular heart disease is a major cause of mortality and morbidity. Revealing the cellular processes and molecules that regulate valve formation and remodeling is required to develop effective therapies. A key step in valve formation during heart development is the epithelial-mesenchymal transformation (EMT) of a subpopulation of endocardial cells in the atrioventricular cushion (AVC). The type III transforming growth factor-β receptor (TGFβR3) regulates AVC endocardial cell EMT in vitro and mes ...[more]

PMID: 21212630

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Project description:BackgroundAirway remodelling is thought to be under the control of a complex group of molecules belonging to the transforming growth factor (TGF)-superfamily. The bone morphogenetic proteins (BMPs) belong to this family and have been shown to regulate fibrosis in kidney and liver diseases. However, the role of BMPs in lung remodelling remains unclear. BMPs may regulate tissue remodelling in asthma by controlling TGF-beta-induced profibrotic functions in lung fibroblasts.MethodsCell cultures were exposed to TGF-beta1 alone or in the presence of BMP-4 or BMP-7; control cultures were exposed to medium only. Cell proliferation was assessed by quantification of the incorporation of [3H]-thymidine. The expression of the mRNA encoding collagen type I and IV, tenascin C and fibronectin in normal human lung fibroblasts (NHLF) was determined by real-time quantitative PCR and the main results were confirmed by ELISA. Cell differentiation was determined by the analysis of the expression of alpha-smooth muscle actin (alpha-SMA) by western blot and immunohistochemistry. The effect on matrix metalloproteinase (MMP) activity was assessed by zymography.ResultsWe have demonstrated TGF-beta1 induced upregulation of mRNAs encoding the extracellular matrix proteins, tenascin C, fibronectin and collagen type I and IV when compared to unstimulated NHLF, and confirmed these results at the protein level. BMP-4, but not BMP-7, reduced TGF-beta1-induced extracellular matrix protein production. TGF-beta1 induced an increase in the activity of the pro-form of MMP-2 which was inhibited by BMP-7 but not BMP-4. Both BMP-4 and BMP-7 downregulated TGF-beta1-induced MMP-13 release compared to untreated and TGF-beta1-treated cells. TGF-beta1 also induced a myofibroblast-like transformation which was partially inhibited by BMP-7 but not BMP-4.ConclusionsOur study suggests that some regulatory properties of BMP-7 may be tissue or cell type specific and unveil a potential regulatory role for BMP-4 in the regulation of lung fibroblast function.

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BMP-2 and TGF?2 shared pathways regulate endocardial cell transformation.

Publications

BMP-2 and TGFβ2 shared pathways regulate endocardial cell transformation.

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