Page 33 - Physico-Chemical Niche Conditions for Bone Cells

Both osteocytes and MuSCs respond to growth factors and cytokines which have been reviewed extensively [37,38], and alter intracellular signaling via tyrosine kinase receptors [39]. These factors may enter the ECM in an autocrine, paracrine, or endocrine manner. Other soluble factors that affect osteocyte and MuSC fate and function are metabolites, e.g. amino acids and vitamin D, and chemical elements, e.g. oxygen and its metabolites (i.e. nitrogen and oxygen-derived reactive oxygen species) [40].
ECM structural components
The concept of ECM regulating cells is long-standing. The ECM provides a three-dimensional (3D) microenvironment for the cells. It is composed of collagens, fibronectin, elastin, laminin, glycosaminoglycans, and several other glycoproteins [41]. ECM provides many signaling molecules that modulate cell behavior and function, as well as triggers biological activities important in organ or tissue development and homeostasis [41]. Osteocytes are involved in the development and maintenance of the ECM in which they are embedded. For mature osteocytes it is particularly important to precisely regulate the amount of calcification around the cell bodies and extensions. In healthy osteocytes there is a persistent matrix and fluid- filled gap of 50-80 nm between the calcified matrix and the cell membrane [42], which is of crucial importance for the transport of nutrients and oxygen through facilitated diffusion, and the transduction of mechanical signals. Early osteocytes, which are embedded in a collagen matrix that is not completely calcified, are also responding to mechanical loading [24]. In local mineralization regulated by osteocytes, there are several key proteins involved, e.g. DMP1, PHEX, MEPE, cathepsin K, and carbonic anhydrase [43,44]. DMP1 is specifically expressed in the canaliculi of osteocytes, and is secreted in the initial stages of mineralized matrix formation in bone [43]. PHEX is located on the membrane of osteoblasts and osteocytes and interacts extensively with DMP1 [43]. The small integrin-binding ligand N-linked glycoprotein family member MEPE is a marker of mature osteocytes and plays a role in the regulation of local matrix mineralization [43]. Cathepsin K and carbonic anhydrase are involved in osteocytic osteolysis, a process in which osteocytes remove calcified matrix in response to stimuli such as parathyroid hormone (PTH). The constituents of the matrix directly surrounding osteocytes has not been exactly defined, but proteins such as bone gamma-carboxyglutamic acid containing protein and noncollagenous proteins (i.e. osteopontin, osteocalcin, osteonectin, biglycan) have been shown to be present [45,46].
The niche of MuSCs is created by ECM proteins, the vascular system, muscle residence cells, and muscle fibers [47]. This 3D-structure surrounding each muscle fiber regulates cell-cell adhesion via integrin receptors, increases the intermolecular binding to activate signaling pathway mechanisms in the myogenetic process, and provides support for force transduction in or between cells [47]. So, it is necessary for bone and muscle cells to
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