Abstract
The physical mechanism by which cells sense high-frequency mechanical signals of small magnitude is unknown. During exposure to vibrations, cell populations within a bone are subjected not only to acceleratory motions but also to fluid shear as a result of fluid-cell interactions. We explored displacements of the cell nucleus during exposure to vibrations with a finite element (FE) model and tested in vitro whether vibrations can affect osteocyte communication independent of fluid shear. Osteocyte like MLO-Y4 cells were subjected to vibrations at acceleration magnitudes of 0.15 g and 1 g and frequencies of 30 Hz and 100 Hz. Gap junctional intracellular communication (GJIC) in response to these four individual vibration regimes was investigated. The FE model demonstrated that vibration induced dynamic accelerations caused larger relative nuclear displacement than fluid shear. Across the four regimes, vibrations significantly increased GJIC between osteocytes by 25%. Enhanced GJIC was independent of vibration induced fluid shear; there were no differences in GJIC between the four different vibration regimes even though differences in fluid shear generated by the four regimes varied 23-fold. Vibration induced increases in GJIC were not associated with altered connexin 43 (Cx43) mRNA or protein levels, but were dependent on Akt activation. Combined, the in silico and in vitro experiments suggest that externally applied vibrations caused nuclear motions and that large differences in fluid shear did not influence nuclear motion (<1%) or GJIC, perhaps indicating that vibration induced nuclear motions may directly increase GJIC. Whether the increase in GJIC is instrumental in modulating anabolic and anti-catabolic processes associated with the application of vibrations remains to be determined.
Highlights
Gap junctions formed by connexins play an important role in cell signaling and tissue function by enabling the passing of ions and intracellular signaling molecules via transmembrane channels in various organ systems [1,2,3]
Connexin 43 can serve as an open ended hemi-channel to secrete signaling molecules such as NO, PGE2 and Ca2+ [9,10,11,12,13] or provide functional communication between resident bone cells via gap junctions, a process that is critical for coordinating bone remodeling and cell function [14,15,16,17,18,19]
Nuclear motions determined by finite element modeling To explore cellular deformations during vibration, we generated a FE model of an elastic cell
Summary
Gap junctions formed by connexins play an important role in cell signaling and tissue function by enabling the passing of ions and intracellular signaling molecules via transmembrane channels in various organ systems [1,2,3]. Gap junctional intercellular communication (GJIC) is important for cell mechanotransduction. Both fluid shear stress and mechanical strain increase GJIC between bone cells [20,21,22,23]. Consistent with the hypothesis of osteocytes being the sensory cells that orchestrate the response of osteoblastic and osteoclastic effector cells [24,25,26], mechanical perturbation of osteocytes can regulate osteoblast function through gap junctions [27]. GJIC may play an important role in relaying mechanically derived signals to other cells such as osteoblasts [28] or vice versa
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