## 2 Mechanotransduction
At present, at least three general models have been proposed in order to explain how cells can \"sense\" these deformations. A first model can be described by the presence of mechanosensor proteins tethered to cell-cell interaction or cell-extracellular matrix (ECM) interaction, which can feel the deformation of the cellular structure, generating biological signals. The conformational changes in the mechanosensor proteins expose different binding site for other proteins [45]. This model is also called the \"_Tethered Model_\". Figure 1: Role of osteoclasts in osteoporosis and the inhibiting effects of mechanical load, gravity, and physical activity. Bone resorption is performed by osteoclasts when activated by certain cytokines, hormones, and the absence of mechanical stimulation (load, gravity, physical activity). In these conditions, cathepsins, H\({}^{+}\)-dependent plasmammembrane ATP-ase and \(\alpha_{5}\beta_{1}\) integrin are expressed. The \(\alpha_{5}\beta_{1}\) integrin interact with the extracellular matrix (ECM) molecules of the mineralized bone matrix, forming a segregated vacuole, where cathepsins and protons are secreted; cathepsins are activated by an acidic environment, demolishing mineralized matrix lining the segregated vacuole. Mechanical forces, including gravity, estrogen, TGF-\(\beta\), and certain cytokine signalling, reduce or block the expression of integrin, proton pump, and cathepsin, preventing the digestion of the bone matrix. On the other hand, it is well known that absence of estrogen signalling (menopause), physical activity (sedentary life style), and gravity (microgravity) are conditions highly favouring osteoporosis. In the second model, deformations result directly in an activation of the enzymatic/signalling activity of the proteins that can convert this modification in biological signals. Finally, a mechanical deformation of the cells can cause a change in the lipid bilayer altering protein-protein interactions, enzymatic activity and architectural intracellular organization. This last model is also called the \"_lipid bilayer model_\" [46]. Nevertheless, in the human organisms, several molecular structures have been identified or proposed that are able to primarily \"sense\" mechanical forces, such as cytoskeleton, extra-cellular matrix, adhesion receptors, extracellular ligands, ion channels, membrane proteins, nuclear pore complex, integrins, G protein coupled-receptors, growth factor receptors etc. [47; 48]. In these structures a number of molecules have been identified as \"mechanosensory\" or \"graviereceptors\", especially those proteins that show a new conformational state after hyper/hypo-gravity stimuli and that are able to transmit a biochemical signal in the cell, causing adaptation of the cellular functions. Additionally, it has been observed that mechanical cues can also cause post-translational modification, intracellular protein shuttling, protein unfolding generating new interactions, and complex pathobiological effects [49; 50; 51; 52; 53; 54]. One of the first site of mechanosensing tightly binds the cellular membrane to the extra-cellular matrix through focal adhesions structure (FAs), characterized by a transmembrane anchoring protein block that establishes complex intracellular relationships with the cytoskeleton. The intracellular part of FA is strictly connected with scaffolding, docking, and signalling (kinases) proteins establishing complex functional and structural connections among the ECM, cell membrane, and cytoskeleton for maintenance of cell shape, internal distribution, and movements of organelles and correct cell proliferation [55]. Focal adhesions are composed by integral proteins, enzymes, and other accessory proteins, some of which can primarily sense mechanical stress. The integral proteins have the role to interact with molecules of the ECM, such as Fibronectin, Vitronectin, Collagen and Laminins, and other ECM molecules.