Читать книгу Biological Mechanisms of Tooth Movement - Группа авторов - Страница 45

The ECM provides a scaffold for cell adhesion, which can occur in two ways: by hemidesmosomes, connecting the ECM to intermediate filaments such as keratin, and by focal adhesions, connecting the ECM to actin filaments within the cell. The latter is the most important for OTM. In both types of adhesion, specific cellular adhesion molecules known as integrins are essential (Barczyk et al., 2013; Walko et al., 2015).

Integrins are transmembrane proteins formed as heterodimers of specific α and β transmembrane proteins that bind cells to ECM structures (Figure 3.5). Integrins can contain many combinations of 18 different α subunits and eight β subunits. For example, osteoblasts have mainly α2β1 integrins, and osteoclasts have mainly αVβ3 integrins (Duong et al., 2000).

Integrins act as receptors for ECM glycoproteins such as fibronectin, vitronectin, and proteins such as collagen and laminin, which contain the amino acid sequence arginine, glycine, aspartate (RGD motif). They can also bind to integrins on the surface of other cells (Duong et al., 2000; Kechagia et al., 2019)

Intracellularly, integrins induce the formation of focal adhesion complexes which consist of the intracellular part of the integrins, focal adhesion kinase, which triggers intracellular mechanotransduction, by activating downstream mechanotransducers and many cytoplasmic proteins, such as tallin, vinculin, paxillin, and alpha‐actinin (Figure 3.6)

The focal adhesion complex binds the integrin to actin filaments, the most important constituent of the cytoskeleton (Meikle, 2006; Martino et al., 2018). Focal adhesions as well as the cytoskeleton are constantly remodeled under the influence of the ECM: proteins associate and disassociate with it continually as signals are transmitted to other parts of the cell. Furthermore, the cytoskeleton can contract by F‐actin sliding on the motor protein myosin II. These processes are responsible for cell deformation and cell migration (Burridge and Chrzanowska‐Wodnicka, 1996). Gradients of different environmental cues, such as diffusible ligands (chemotaxis), substrate‐bound ligands in the ECM (haptotaxis), or ECM rigidity (durotaxis) dictate the direction of migration (Kechagia et al., 2019).

Figure 3.5 Integrin and its subunits.

(Source: Jaap Maltha.)

Figure 3.6 The focal adhesion complex.

(Source: Jaap Maltha.)

Figure 3.7 The nucleus‐related part of the cytoskeleton.

(Source: Jaap Maltha.)

It is essential that the composition and the distribution of the focal adhesions within a cell change to allow its migration. Initially, new focal adhesion complexes and cytoskeletal structures are formed at cellular protrusions, the lamellipodia. They mature and remain stationary with respect to the ECM through integrins. The cell uses this as an anchor on which it can push or pull itself over the ECM. At the same time, focal adhesion complexes at the trailing edge are disassembled, together with the cytoskeletal structures, allowing cell migration along the ECM (Martino et al., 2018; Kechagia et al., 2019).

Furthermore, the cytoskeleton is linked to the nuclear envelope by SUN and nesprin proteins. They transfer mechanical stimuli from the cytoskeleton to the nucleus where mechanosensitive transcription factors activate mechanosensitive genes (Feller et al., 2015; Martino et al., 2018) (Figure 3.7).