Page 32 - Physico-Chemical Niche Conditions for Bone Cells

Physicochemical niche conditions and mechanosensing
MuSCs modulate the extracellular niche condition of the myofiber via inhibiting the function of fibroblasts during skeletal muscle remodeling [31]. Myofiber type transition and reduction in muscle force generation capacity are highly correlated with NMJ disruption and effects of sciatic nerve transection are aggravated upon MuSC depletion [31]. The NMJ may affect the MuSC indirectly via its effect on the myofiber and the fibroblast but there may also be a direct interaction between the NMJ and the MuSCs [32]. Generally, MuSCs can interact with various cell types, e.g. macrophages, FAPs, regulatory T cells, endothelial cells, apelin, periostin, and oncostatin M [33].
Chemical Niche Conditions for (Early)-Osteocytes and Myoblasts
Here we define chemical niche conditions as the non-cell bound chemical cues that are consistently available in the extracellular environment of a specific cell, and may affect the biological function of that cell. The most obvious example would be the chemical makeup of the ECM to which a cell is anchored (i.e. the available epitopes, defining the integrins which a cell can use to connect to the environment), but autocrine and paracrine soluble factors, and small molecules such as O2 and in case of bone also soluble calcium ions are good examples of chemical factors defining the niche conditions of bone and muscle cells.
Cells adhere to their substrate through integrins, which are frequently organized in focal adhesions. These focal adhesions serve as cytoskeletal anchor points connecting integrin clusters and actin filaments, which allow the transduction of both chemical and physical extracellular cues from the ECM across the membrane to the intracellular environment, and the other way around. Integrins consist of 18 a and eight β subunits which assemble into 24 different receptors with an N-terminal head and extended C-terminal legs [34]. Their constitution depends on epitopes in the ECM. Thus, by understanding which integrins are present on a specific cell type, one can deduce which ECM proteins are available in the vicinity of a cell, that drive cell behavior. Osteocytes contain β1 integrin [35], β3 integrin [36], and avβ3 integrin [36]. In addition to integrins, unidentified molecules with a remarkable consistent length of ~100 nm connect the osteocyte cell membrane to the wall of the canaliculus. MuScs contain amongst others β1-integrin, a7-integrin, and β5-integrin. To the best of our knowledge very little is known regarding the integrin mechanosensors in early osteocytes. Myoblasts also contain dystrophin, which is a cohesive protein linking actin filaments to other support proteins that reside on the sarcolemma. Dystroglycan is a dystrophin-associated glycoprotein, which anchors specifically to laminin in the basement membrane. In this way, the dystroglycan complex, which links the ECM to the intracellular actin filaments, provides structural integrity in muscle tissue. Key ligands in the ECM that bind to integrins and dystroglycans are fibronectin, laminin, and collagen.
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