BMP signaling in skeletal muscle and bone

Since their discovery as bone inducers, Bone Morphogenetic Proteins (BMPs) have been demonstrated to control multiple functions during embryogenesis as well as postnatally. BMPs are acting as morphogenes, i.e. they can induce various cell fates at different concentrations. There are multiple regulatory mechanisms to control BMP signaling and dysregulated BMP signaling is pathologically linked with multiple diseases. This thesis presents novel studies regarding the role of elevated BMP signaling on the progression of two different genetic diseases, i.e. Fibrodysplasia Ossificans Progressiva (FOP) and Duchenne Muscular Dystrophy (DMD).\nBesides that, BMP signaling is tightly regulated on different levels; the activity of BMP signaling can also be modulated by other signaling pathways, such as the TGFβ and Wnt signaling pathways. In Chapter 2, we investigated the molecular mechanisms underlying TGFβ and BMP-induced conversion of endothelial cells into osteoblasts. In Chapter 3, using the BMP antagonist Noggin, we studied the role of BMP signaling in the progression of DMD disease. In Chapter 4, we described that Id3 is activated by canonical Wnt signaling in C2C12 cells, and mediates Wnt-induced myoblast proliferation and osteoblast differentiation. In Chapter 5, we showed that BMP6, in contrary to BMP7, BMP2 and BMP4, cannot be inhibited by Noggin, and identified the crucial amino acid that endows BMP6 resistance to Noggin inhibition. These findings make it possible to engineer BMPs with superior agonist activity through amino acid substitution. In Chapter 6, using exon skipping technology, we obtained an antisense oligonucleotide (AON) that specifically targets BMP type I receptor activin receptor-like kinase (ALK) 2. The ALK2 AON was shown to decrease ALK2 expression and reduced BMP6 induced osteoblast differentiation in vitro. Finally in Chapter 7, the results presented in the thesis were discussed and suggestions for future research were provided.