Figure 9

The scheme summarises different intracellular pathways during osteoblast differentiation which include promoting (blue) and inhibiting (red) factors and are mainly mediated by Smad proteins. Based on recent studies it can be assumed that not only the TGFβ/BMP, the Wnt/beta-catenin, the Notch pathway or direct gene activations by steroids but also prostaglandins are involved in osteoblast differentiation. Prostacyclin and its related molecules, such as iloprost, play a crucial role in various cellular mechanisms and control intracellular signals: the IP receptor mediates the actions of its ligand via Gs (or G_q, G₁₁, G_i) protein activation leading to adenylate cyclase activation followed by an intracellular increase of cAMP. Moreover, the human IP receptor gene presents various bindings sites such as glucocorticoid response element (GRE) and it can be concluded that glucocorticoids also regulate its expression. In addition, the human EP receptors with its various subtypes such as EP_1–4 and their isoforms are also activated by iloprost. One major EP-related effect is the mobilisation of intracellular Ca²⁺ but also a down-regulation of intracellular cAMP concentration as described for the EP₄ receptor. However, the complex intracellular effects that are triggered by iloprost and the importance in osteoblast differentiation are poorly understood to date.