Figure 2
BMP signaling in bone. BMP activity is antagonized by cognate binding proteins, including Noggin, Grem1, Chordin, CHL, and Fellistatin. BMPs bind to homomeric type II receptors, which transphosphorylases homomeric type I receptor to induce Smad-dependent and non-Smad-dependent signaling. In the Smad-dependent signaling, phosphorylated R-Smad (Smad1, 5, or 8) complexes with Smad4 and co-translocates into the nuclei, where they recruit co-factors and Runx2 to regulate osteogenic gene expression, for example, Runx2, Dlx5, and Osx. In the non-Smad-dependent pathway, phosphorylated TAK1 recruit TAB1 to initiate the MKK-p38 MAPK or MKK–ERK1/2 signaling cascade. MAPK phosphorylates Runx2, Dlx5, and Osx to promote their transcriptional activity. MAPK also phosphorylates Runx2 to promote the formation of Smad–Runx2 complex. I-Smad (Smad6 or 7) negatively regulates Smad signaling by preventing R-Smad phosphorylation, targeting R-Smad or type I receptor for ubiquitin–proteasome degradation with Smurf1 and inhibiting R-smad/co-Smad complex nuclei translocation. Arkadia positively regulates Smad signaling by targeting I-Smads for ubiquitin–proteasome degradation. Ubc9/SUMO complex negatively regulates Smad signaling by targeting Smad4 for ubiquitin–proteasome degradation. BMP–Smad signaling promotes almost every step during osteoblast differentiation and maturation. BMP, bone morphogenetic protein.
