Perhaps the most straight-forward explanation for how the BMP and activin/TGF-β signaling pathways lead to opposite cellular outcomes would be inversely controlling target gene expression. This mechanism can be thought of like a light switch—with one pathway turning the gene on while the other turns the gene off. This switchlike activity has been demonstrated in several cellular contexts for certain target genes. For instance, TGF-β signaling upregulates the expression of endothelin-1 (
ET-1), connective tissue growth factor (
CTGF), plasminogen activator inhibitor-1 (
PAI-1), e-cadherin, and S100 calcium-binding protein a4 (
S100A4), but BMP7 downregulates these same targets.
56,60-62 Similar data exist demonstrating the ability of BMP2 to downregulate activin/TGF-β target genes,
23,63 likely indicating a general effect of the BMP pathway rather than BMP ligand specific. The reciprocal relationship has also been demonstrated wherein BMP2-induced genes are downregulated by TGF-β or activin.
23,64 Differential gene regulation likely explains the antagonism between these pathways in certain scenarios; however, we believe it has important limitations. The target genes of the BMP and activin/TGF-β pathways vary widely by physiologic context for reasons that are poorly understood,
65 thus making it difficult to conceive that the reciprocal relationship is consistently maintained. For instance, although BMP and TGF-β oppositely regulate the expression of the inhibitor of differentiation-1 gene (
ID1), both pathways can also upregulate
ID1 expression
66,67; said differently,
ID1 expression may be controlled by an “on/on” switch in certain scenarios. Numerous additional examples exist of gene targets that are shared by both pathways while, simultaneously, others are inversely regulated.
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