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BMP-7/TGF-β1 signalling in myoblasts: components involved in signalling and BMP-7-dependent blockage of
Steffen K Meurer1, Marcel Esser, Lidia Tihaa
1The Institute of Clinical Chemistry and Pathobiochemistry, RWTH University Hospital, Pauwelsstr. 30, D-52074 Aachen, Germany. smeurer@ukaachen.de
Abstract:
We and others have recently described the antagonistic role of Bone morphogenetic protein-7 (BMP-7) in TGF-β signalling and myogenic differentiation. To specify the underlying mechanism(s), we here analysed the expression and function of the individual components mediating TGF-β1 and BMP-7 responses. We found that BMP-7 at a concentration of 25 ng/ml induces signalling exclusively via ALK2 and ALK3 leading to the activation of Smad1 and Smad5 and subsequent expression of Id proteins. In contrast, low doses of TGF-β1 (0.1 ng/ml) lead to an exclusive activation of ALK5 and phosphorylation of Smad2 and Smad3 that regulate specific target genes including connective tissue growth factor (CTGF). CTGF is rapidly induced by TGF-β1 already 1h after stimulation and reduced by BMP-7 application. Smad1/Smad5 or Id1/2 overexpression reduced the TGF-β1-mediated expression of CTGF. However, although siRNA-mediated knock down of Alk2/3 or Smad1/5 counteracts the BMP-7 effect on basal CTGF expression there was no consistent reversion of the observed BMP-7 effect on TGF-β1-mediated CTGF expression. Moreover, ALK5 inhibition using the SB431542 inhibitor significantly affected CTGF expression only at later time points whereas ERK1/2 inhibition completely abrogated CTGF expression. These findings point towards a regulatory role of BMP-7 that relies on modulation of Mitogen-activated protein kinases rather than mechanisms that are exclusively driven by differential Smad activation.
Insights
Bone morphogenetic protein-7 (BMP-7) antagonizes TGF-β1 signaling by modulating Mitogen-activated protein kinases, not solely through Smad activation, impacting connective tissue growth factor (CTGF) expression.
Area of Science:
- Cellular and Molecular Biology
- Signal Transduction Pathways
- Protein Interactions
Background:
- Bone morphogenetic protein-7 (BMP-7) is known to antagonize transforming growth factor-beta (TGF-β) signaling and myogenic differentiation.
- The precise molecular mechanisms underlying BMP-7's antagonistic role require further elucidation.
Purpose of the Study:
- To investigate the specific mechanisms by which BMP-7 modulates TGF-β1 signaling.
- To analyze the roles of individual signaling components in mediating TGF-β1 and BMP-7 responses.
- To determine the impact of BMP-7 on connective tissue growth factor (CTGF) expression and its regulation.
Main Methods:
- Analysis of gene and protein expression in response to TGF-β1 and BMP-7 stimulation.
- Overexpression and knockdown studies using Smad and Id proteins, as well as ALK2/3 and Smad1/5.
- Inhibition studies using SB431542 (ALK5 inhibitor) and ERK1/2 inhibitors.
- Measurement of CTGF expression at various time points post-stimulation.
Main Results:
- BMP-7 (25 ng/ml) exclusively activates ALK2/3, leading to Smad1/5 and Id protein activation.
- Low-dose TGF-β1 (0.1 ng/ml) exclusively activates ALK5, phosphorylating Smad2/3 and inducing CTGF.
- BMP-7 reduces TGF-β1-induced CTGF expression; Smad1/5 or Id1/2 overexpression partially reduces CTGF.
- siRNA knockdown of ALK2/3 or Smad1/5 counteracts BMP-7's effect on basal CTGF but not TGF-β1-mediated CTGF.
- ALK5 inhibition affects CTGF later; ERK1/2 inhibition abrogates CTGF expression.
Conclusions:
- BMP-7's antagonistic role in TGF-β1 signaling is primarily mediated through the modulation of Mitogen-activated protein kinases (MAPKs).
- Differential Smad activation alone does not fully explain BMP-7's regulatory effects on CTGF expression.
- These findings highlight a complex interplay between BMP-7, TGF-β1, Smad, and MAPK pathways in regulating gene expression.
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