Background: TGF-beta is one of the key cytokines implicated in various disease processes including cancer. TGF-beta inhibits growth and promotes apoptosis in normal epithelial cells and in contrast, acts as a pro-tumour cytokine by promoting tumour angiogenesis, immune-escape and metastasis. It is not clear if various actions of TGF-beta on normal and tumour cells are due to differential gene regulations. Hence we studied the regulation of gene expression by TGF-beta in normal and cancer cells.

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Bone morphogenetic protein (BMP) signaling is known to support differentiation of human embryonic stem cells (hESCs) into mesoderm and extraembryonic lineages, whereas other signaling pathways can largely influence this lineage specification. Here, we set out to reinvestigate the influence of ACTIVIN/NODAL and fibroblast growth factor (FGF) pathways on the lineage choices made by hESCs during BMP4-driven differentiation. We show that BMP activation, coupled with inhibition of both ACTIVIN/NODAL and FGF signaling, induces differentiation of hESCs, specifically to bhCG hormone-secreting multinucleated syncytiotrophoblast and does not support induction of embryonic and extraembryonic lineages, extravillous trophoblast, and primitive endoderm. It has been previously reported that FGF2 can switch BMP4-induced hESC differentiation outcome to mesendoderm. Here, we show that FGF inhibition alone, or in combination with either ACTIVIN/NODAL inhibition or BMP activation, supports hESC differentiation to hCG-secreting syncytiotrophoblast. We show that the inhibition of the FGF pathway acts as a key in directing BMP4-mediated hESC differentiation to syncytiotrophoblast.

The family of bone morphogenetic proteins (BMPs) comprises approximately 30 secreted cytokines that signal through transmembrane serine/threonine kinase receptors. The BMP signaling pathways are fine-tuned on multiple levels: Extracellular antagonists modify ligand activity; several co-receptors enhance or inhibit downstream signaling events through multiple mechanisms; and intracellular molecules further regulate the signaling outcome and mediate crosstalk with other pathways. BMPs affect structures and processes throughout the entire body, ranging from embryonic patterning and development through stem cells and their niches, to tissue homeostasis and regeneration. This comprehensive involvement in various tissues had not been expected by Marshall Urist, who initially discovered the ability of an unknown factor in bone to induce bone growth in muscle and subsequently suggested the name "bone morphogenetic protein." Today, recombinant BMPs are used in clinical practice for the treatment of bone and kidney disorders, and new genetically modified BMPs are emerging as promising tools in regenerative medicine and tissue engineering. Clearly, the functions of BMPs within the body are more versatile than initially suspected. To discuss modern trends in BMP signaling, leaders in the field met for the First International BMP Workshop in Berlin in September 2009. Here, we summarize new insights on the roles of BMPs in various tissues and highlight recent findings in cell, structural, and developmental biology as well as the therapeutic potential of BMPs. Finally, we conclude that BMPs today deserve to be called body morphogenetic proteins.

MicroRNAs play important roles during cell reprogramming and differentiation. In this study, we identified the miR-497$195 cluster, a member of the miR-15 family, as strongly upregulated with age of postnatal bone development in vivo and late differentiation stages of primary osteoblasts cultured in vitro. Early expression of miR-195-5p inhibits differentiation and mineralization. Microarray analyses along with quantitative PCR demonstrate that miR-195-5p alters the gene regulatory network of osteoblast differentiation and impairs the induction of bone morphogenetic protein (BMP) responsive genes. Applying reporter gene and Western blot assays, we show that miR-195-5p interferes with the BMP/Smad-pathway in a dose-dependent manner. Systematically comparing the changes in mRNA levels in response to miR-195-5p overexpression with the changes observed in the natural course of osteoblast differentiation, we demonstrate that microRNAs of the miR-15 family affect several target genes involved in BMP signaling. Predicted targets including Furin, a protease that cleaves pro-forms, genes encoding receptors such as Acvr2a, Bmp1a, Dies1, and Tgfbr3, molecules within the cascade like Smad5, transcriptional regulators like Ski and Zfp423 as well as Mapk3 and Smurf1 were validated by quantitative PCR. Taken together, our data strongly suggest that miR-497$195 cluster microRNAs act as intracellular antagonists of BMP signaling in bone cells.