# Static Osteogenesis versus Dynamic Osteogenesis:
## 2 Structural and Functional Differences between SO and DO
In particular, vascular endothelial growth factor (VEGF), a main player in angiogenesis, is capable of provoking the migration and proliferation of endothelial cells and indirectly stimulating osteogenesis through the regulation of the osteogenic growth factors released through paracrine signaling [12]. Moreover, in studies on bone healing, it was shown that osteoblast differentiation could also depend on platelet-derived growth factor (PDGF) [22; 23; 24]. In a study concerning genetic manipulations in mice, [PERSON] and coworkers [25] recently highlighted the critical role of the hypoxia-inducible-factor/vascular endothelial growth factor (HIF) pathway in coupling angiogenesis and osteogenesis. Briefly, SO is triggered by inductive stimuli. Since during SO the bone matrix is laid down without preexistent osteocytes, we believe that the irregular arrangement and polarization of the osteoblasts in stationary osteogenic cords probably depends on a lack of osteocyte guidance. Only after SO, does DO occurs by means of movable osteoblastic laminae. These DO osteoblasts are likely guided by SO osteocytes (inside the preliminary SO bony trabeculae) and are also capable of \"sensing\" the vessels (towards which they move) through the stromal cells located between the migrating laminae of the bone-growing surfaces and the vascular endothelia [26]. To summarize, SO is in fact a form of neo-osteogenesis, in the sense that it occurs in mesenchymal tissue (for example during intramembranous ossification of the cranial vault) in which pre-existing bone is lacking and therefore there are no osteocytes that can act as  
Figure 4: SEM micrographs showing the morphology of SO/DO osteocytes. (**A**) SO osteocytes have a globous shape, and their short dendrites radiate all around the cell body. (**B**) DO osteocytes display an almond-like shaped cell body and two different types of cytoplasmic processes: the short “mineral-facing” dendrites (red arrows) and the long/sender “vascular-facing” dendrites (white arrows). The square areas show the mean values of osteocyte cell body axes; the almost spherical morphology of SO osteocytes with respect to the triaxial ellipsoidal shape of the DO osteocytes can be seen. mechanosensors to guide the subsequent osteogenesis. In tissues where SO occurs, the absence of mechano-sensors makes mechanical stresses completely irrelevant since they cannot be perceived. It follows that the SO can only be induced by cytokines released by the endothelial cells; it is therefore to be considered a typical process of osseoinduction which is mechanically independent. Conversely, DO occurs on the surfaces of a pre-existing bone containing osteocytes (Figure 6), which perceive the deformations induced in the bone matrix by mechanical loading. Therefore, in DO mechanical factors can play a pivotal role in triggering and directing the activity of osteoblasts (Figure 7). It is thus to be considered a process of osseoconduction which is strongly influenced by mechanical stress [27]. Besides the described differences, SO and DO also occur with diverse speeds: in SO, bone matrix is generally produced very rapidly, while in DO the events proceed over a longer period of time. Thus, the former allows for the formation of a preliminary network of trabecular woven bone (surrounding wide primitive vascular spaces), which has a supporting function for subsequent lamellar bone apposition by typical movable osteoblasts (Figure 8); this in turn allows SO trabeculae thickening by DO and consequently the narrowing of the primitive vascular haversian spaces, giving rise to primary osteons (i.e., bone compaction) (Figure 9). In this regard, it should be underlined that SO and DO also differ in the involvement of the apoptosis occurring adjacent to the sites of osteogenesis: this is more frequently observed during DO than during SO, because in this context apoptosis is mainly dedicated to making space for advancing bone osteogenesis.