Page 15 - Physico-Chemical Niche Conditions for Bone Cells

differentiation, migration, proliferation, transcription, and translation [29]. It has been demonstrated that there are four critical factors for matrix mineralization, including the presence of collagen type I, availability of phosphate, removal of pyrophosphate, and absence of other inhibitors of mineralization [35]. The distribution and epitopes of peptides located in the matrix are also important for cell interactions with the matrix environment [36]. Biomaterials with RGD coating provide an active site to control the communication of cell/tissue and material interface, and achieve a bioactive implant [37]. Therefore, RGD is an important biochemical molecule to be used, e.g. in the area of bone tissue engineering. The spatial distribution and density of RGD-containing peptide epitopes decide the extent of receptor activation and clustering [36,38]. The conformation and (bio)chemical properties of these peptide epitopes (e.g. charge and hydrophobicity) in the matrix determine the specificity of cell recognition by integrins [36,38].
Mechanosensing and mechanotransduction in bone cells
The nucleus-cytoskeleton-integrin-extracellular matrix system is crucial to sense exterior mechanical forces and to transduce these forces from the matrix all the way to the nucleus [39]. This system comprises the interactions between the molecules of the extracellular or pericellular matrix (e.g. collagen, fibrils, and fibronectin), the subunits of integrins, the cytoskeleton and associated proteins (e.g. paxillin, talin, vinculin, a-actinin, actin, microtubules, and intermediate filaments), and the nuclear membrane [39] (Fig. 1). Integrins are transmembrane receptors that facilitate cell-extracellular matrix adhesion, and in some blood cell types cell-cell contacts. Integrins, as mechanosensors, provide high-affinity sites for biochemical reactions caused by mechanical forces [40]. The b1 subunit-containing integrins are the major matrix-binding integrins, which connect to fibronectin (a4b1, a5b1, a5b3, avb3), collagens (a1b1, a2b1, a10b1, a11b1), and laminins (a3b1,a6b1, a7b1) [36]. The b2 subunit- containing integrins are involved in the interaction between cells [36]. The β3 subunit- containing integrins are a heterogeneous group, of which a3b3 and avb3 can recognize the RGD peptide sequence [36,41]. Different integrins are expressed by different cell types, such as a1, a3, and b1 integrins by osteoblasts, and avb3 integrins by osteocytes, although there is also overlap, e.g. osteocytes also express b1 containing integrins [41–43]. Focal adhesions (FA), which are considered specialized transducers of a mechanical signal into a biochemical signal, interact with integrins, undergo changes in structure, and cause autophosphorylation at Tyr-397 (tyrosine residue 397). This promotes FA to combine with Src or PI3K (phosphatidylinositol 3-kinase), and activate FA/PI3K/Akt/NF-kB and FA-Src/Grb2/Sos/Ras- Raf/MEK/ERK-1/2 pathways. Those pathways then change cell function [40]. Integrins interact with the actin-cytoskeleton via FA (paxillin), talin, and vinculin [44]. The actin-cytoskeleton is
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