Page 39 - Physico-Chemical Niche Conditions for Bone Cells

External mechanical cues
Cells can be subjected to extracellular pressure, tensile force, and shear stress. Internal forces are exerted by traction forces generated by stress fibers of the cytoskeleton, which are attached to focal adhesions within the cell membrane. Pressure on bone affects mechanosensitive osteocytes embedded in the calcified bone matrix to orchestrate bone remodelling to maintain bone homeostasis under normal conditions [87]. Osteocyte-like MLO- Y4 cells can sense cyclic hydraulic pressure of 68 kPa at 0.5 Hz and respond via increasing intracellular Ca2+ concentration and changing microtubule organization. In addition, pressure increases gene expression of COX-2 and the RANKL/OPG ratio while decreasing apoptosis in osteocytes, suggesting that osteocytes play an important role in bone remodeling in vivo [87].
Intuitively one would not expect that osteocytes within bone are subjected to tensile forces and strains. However, bone loading by impact forces causes movement within the bone marrow [88]. Then early osteocytes within uncalcified ECM are also subjected to mechanical loading by movement of their surrounding matrix [24]. In addition to pressure and tensile stress, cells are subjected shear stress when forces exerted onto the cell apex and base are oppositely directed. This occurs when forces are exerted to the apex or base via the ECM or when extracellular fluid or gelatinous matrix is displaced along the cell [89–91]. Due to anchoring and traction forces within the cytoskeleton, an opposite force will create a shear moment. In bone, early osteocytes are likely subject to shear loads, while late osteocytes are subjected to fluid shear stress around their cell processes. In vivo, shear stress in trabecular bone during whole bone loading produces micro-scale interaction between bone marrow and trabecular bone. It affects the distribution of mechanical stress and strain in bone marrow and its cellular components, e.g. hematopoietic stem cells, osteoclasts, pre-osteoclasts, macrophages, etc. [92]. Tatsumi et al. [93] developed a mouse model in which ~80% of the osteocytes are ablated upon injection with diphtheria toxin. The osteocyte-less mice are resistant to unloading-induced bone loss, confirming that viable osteocytes are essential producers of factors that activate osteoclasts in response to unloading. Osteocyte-less mice show an anabolic response to (re)loading of the bones, suggesting that the production of osteo-anabolic factors by mechanically stimulated osteocytes is not essential to achieve an increase in bone mass. This might indicate that osteoblasts or pre-osteocytes are mechanosensitive.
In contrast to bone, within muscle, tensile forces are continuously exerted onto the myofibers. Although it has never been shown that MuSCs in vivo or in situ within their niche are subjected to tensile strains and undergo strain deformations, it is highly likely that such deformations occur [94]. As these cells are mechanically linked to the sarcolemma and the basal lamina, stretching and shortening of the myofiber will likely cause alignment of the MuSC
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