# Molecular Mechanisms of Topography Sensing by Osteoblasts: An Update
## 3 Molecular Mechanisms of Transduction of the Topographical Information  
The discovery that the local geometry may carry information altering the behavior of cells obviously brings about the question of the transduction of that information into biological pathways. The presence of roughness affects the morphology and spreading of osteoblasts. Indeed, osteoblasts spread less on rough titanium [65; 66]. MSCs also exhibit an altered shape with smaller and more elongated cells on rough surfaces [37]. Topography-induced changes in cell shape or elongation are common features of the transduction of topography observed in almost any cell type [67] and generally connect with changes in the cell focal adhesions (FA) and cytoskeleton organization [59; 68]. The modification in integrin mediated adhesion and force generation in response to specific topographies appear to be a key step in the transduction of the topographic signal. Osteogenic surfaces such as microptis, microgrids or microroughness increase the number and/or the size of FA [40; 49; 69; 70; 71], with larger FA being indicative of stronger adhesion and traction forces. Conversely, nonosteogenic topographies like ordered nanopits or micrometric grooves and ridges decreasesthe number or size of FA [72; 73; 74]. The importance of adhesion size is well illustrated by the fact that the impaired osteogenicicity of nanogroves is correlated with the shift of adhesions from large FA to the smaller and more transient focal complexes [75]. These integrin-based adhesions are not mere points of anchorage onto the substrates. Rather, they work as mechanosensitive signaling hubs whose activity can be modulated by the topography (Figure 1). Indeed, osteogenesis-inhibiting topographies like ordered nanopits decrease the expression of the Focal Adhesion Kinase (FAK) [74] while osteogenic surfaces such as micrometric grooves and ridges, nanoroughness or titanium nanotubes increase the amount of phosphorylated FAK, a read-out generally associated with increase FA signaling [40; 70; 76]. The topography-induced changes in adhesion can be explained in part by a direct effect of topography on the level of expression of key integrins. Indeed, osteogenic nanorough surfaces increase the expression of integrin \(\alpha\)V, \(\alpha\)2 and \(\beta\)1, \(\beta\)3 and \(\beta\)5 [26; 29; 70; 77; 78]. Importantly, the knock-down of integrin \(\alpha\)V, \(\beta\)3 or \(\alpha\)2 decreases the expression of osteogenic markers, demonstrating the key role of upstream integrin mediated adhesion in the transduction of the topographical cue [26; 77; 78]. This central role of integrin-mediated adhesion in topography sensing strongly suggests that topography sensing is a specific case of the better known mechanosensing, involved, for instance, in the shear stress-induced or stiffness-induced osteogenicicity [79; 80]. Downstream of integrins, the MAPK pathways, such as the ERK pathway or the p38 pathway, can be activated (Figure 1). They are essential to bone production, as mice expressing constitutively active ERK present Runx2-dependent enhanced bone production in vivo contrary to mice expressing dominant negative forms of ERK [81]. The topography-induced integrin signaling (shown by the increased amount of pFAK) and osteogenicity (illustrated by osteogenic marker expression) are correlated with the upregulation of MAPK-related genes [73; 82; 83]. Consistently, the phosphorylation of ERK increases on osteogenic topographies [76; 84] and the inhibition of ERK and p38 hampers further osteogenic behavior. Another important pathway in the transduction of topographical cues into matrix mineralization are the BMPs (Figure 1). BMPs bind to cell surface BMP receptors and eventually activate transcription factors of the Smad Family [85] that in turn induce the expression of genes involved in osteoblastogenesis and bone formation, such as Runx2 and OSX.