Osteocytes play a pivotal role in the regulation of skeletal mass. Osteocyte processes are thought to sense the flow of interstitial fluid that is driven through the osteocyte canaliculi by mechanical stimuli placed upon bone, but how this flow elicits a cellular response is virtually unknown. Modern theoretical models assume that osteocyte canaliculi contain ultrastructural features that amplify the fluid flow-derived mechanical signal. Unfortunately the calcified bone matrix has considerably hampered studies on the osteocyte process within its canaliculus. Using one of the few ultra high voltage electron microscopes (UHVEM) available worldwide, we applied UHVEM tomography at 2 MeV to reconstruct unique three-dimensional images of osteocyte canaliculi in 1 μm sections of human bone. A realistic three-dimensional image-based model of a single canaliculus was constructed, and the fluid dynamics of a Newtonian fluid flow within the canaliculus was analyzed. We created virtual 2.2 nm thick sections through a canaliculus and found that traditional TEM techniques create a false impression that osteocyte processes are directly attached to the canalicular wall. The canalicular wall had a highly irregular surface and contained protruding axisymmetric structures similar in size and shape to collagen fibrils. We also found that the microscopic surface roughness of the canalicular wall strongly influenced the fluid flow profiles, whereby highly inhomogeneous flow patterns emerged. These inhomogeneous flow patterns may induce deformation of cytoskeletal elements in the osteocyte process, thereby amplifying mechanical signals. Based on these observations, new and realistic models can be developed that will significantly enhance our understanding of the process of mechanotransduction in bone.
In bone functional adaptation by remodelling, osteocytes in the lacuno-canalicular system are believed to play important roles in the mechanosensory system. Under dynamic loading, bone matrix deformation generates an interstitial fluid flow in the lacuno-canalicular system; this flow induces shear stress on the osteocytic process membrane that is known to stimulate the osteocytes. In this sense, the osteocytes behave as mechanosensors and deliver mechanical information to neighbouring cells through the intercellular communication network. In this study, bone remodelling is assumed to be regulated by the mechanical signals collected by the osteocytes. From the viewpoint of multi-scale biomechanics, we propose a mathematical model of trabecular bone remodelling that takes into account the osteocytic mechanosensory network system. Based on this model, a computational simulation of trabecular bone remodelling was conducted for a single trabecula under cyclic uniaxial loading, demonstrating functional adaptation to the applied mechanical loading as a load-bearing construct.
It is well-established that cyclic, but not static, mechanical loading has anabolic effects on bone. However, the function describing the relationship between the loading frequency and the amount of bone adaptation remains unclear. Using a combined experimental and computational approach, this study aimed to investigate whether trabecular bone mechano-regulation is controlled by mechanical signals in the local in vivo environment and dependent on loading frequency. Specifically, by combining in vivo micro-computed tomography (micro-CT) imaging with micro-finite element (micro-FE) analysis, we monitored the changes in microstructural as well as the mechanical in vivo environment [strain energy density (SED) and SED gradient] of mouse caudal vertebrae over 4 weeks of either cyclic loading at varying frequencies of 2, 5, or 10 Hz, respectively, or static loading. Higher values of SED and SED gradient on the local tissue level led to an increased probability of trabecular bone formation and a decreased probability of trabecular bone resorption. In all loading groups, the SED gradient was superior in the determination of local bone formation and resorption events as compared to SED. Cyclic loading induced positive net (re)modeling rates when compared to sham and static loading, mainly due to an increase in mineralizing surface and a decrease in eroded surface. Consequently, bone volume fraction increased over time in 2, 5, and 10 Hz (+15%, +21% and +24%, p ≤ 0.0001), while static loading led to a decrease in bone volume fraction (−9%, p ≤ 0.001). Furthermore, regression analysis revealed a logarithmic relationship between loading frequency and the net change in bone volume fraction over the 4 week observation period ( R 2 = 0.74). In conclusion, these results suggest that trabecular bone adaptation is regulated by mechanical signals in the local in vivo environment and furthermore, that mechano-regulation is logarithmically dependent on loading frequency with frequencies below a certain threshold having catabolic effects, and those above anabolic effects. This study thereby provides valuable insights toward a better understanding of the mechanical signals influencing trabecular bone formation and resorption in the local in vivo environment.
Highlights d Smooth muscle contractions exert high and periodic intrauterine pressures on embryos d Buffer space made by Reichert's membrane protects embryos from intrauterine pressures d Intrauterine pressures are necessary to specify distal visceral endoderm correctly d Reduced pressures restore the deformed shape of Reichert's-membrane-deficient embryos
Bone structure and function are maintained by well-regulated bone metabolism and remodeling. Although the underlying molecular and cellular mechanisms are now being understood, physiological and pathological states of bone are still difficult to predict due to the complexity of intercellular signaling. We have now developed a novel in silico experimental platform, V-Bone, to integratively explore bone remodeling by linking complex microscopic molecular/cellular interactions to macroscopic tissue/organ adaptations. Mechano-biochemical couplings modeled in V-Bone relate bone adaptation to mechanical loading and reproduce metabolic bone diseases such as osteoporosis and osteopetrosis. V-Bone also enables in silico perturbation on a specific signaling molecule to observe bone metabolic dynamics over time. We also demonstrate that this platform provides a powerful way to predict in silico therapeutic effects of drugs against metabolic bone diseases. We anticipate that these in silico experiments will substantially accelerate research into bone metabolism and remodeling.
The process of bone remodeling is regulated by metabolic activities of many bone cells. While osteoclasts and osteoblasts are responsible for bone resorption and formation, respectively, activities of these cells are believed to be controlled by a mechanosensory system of osteocytes embedded in the extracellular bone matrix. Several experimental and theoretical studies have suggested that the strain-derived interstitial fluid flow in lacuno-canalicular porosity serves as the prime mover for bone remodeling. Previously, we constructed a mathematical model for trabecular bone remodeling that interconnects the microscopic cellular activities with the macroscopic morphological changes in trabeculae through the mechanical hierarchy. This model assumes that fluid-induced shear stress acting on osteocyte processes is a driving force for bone remodeling. The validity of this model has been demonstrated with a remodeling simulation using a two-dimensional trabecular model. In this study, to investigate the effects of loading frequency, which is thought to be a significant mechanical factor in bone remodeling, we simulated morphological changes of a three-dimensional single trabecula under cyclic uniaxial loading with various frequencies. The results of the simulation show the trabecula reoriented to the loading direction with the progress of bone remodeling. Furthermore, as the imposed loading frequency increased, the diameter of the trabecula in the equilibrium state was enlarged by remodeling. These results indicate that our simulation model can successfully evaluate the relationship between loading frequency and trabecular bone remodeling.
Poroelasticity is a theory that quantifies the time-dependent mechanical behavior of a fluid-saturated porous medium induced by the interaction between matrix deformation and interstitial fluid flow. Based on this theory, we present an analytical solution of interstitial fluid pressure in poroelastic materials under uniaxial cyclic loading. The solution contains transient and steady-state responses. Both responses depend on two dimensionless parameters: the dimensionless frequency O that stands for the ratio of the characteristic time of the fluid pressure relaxation to that of applied forces, and the dimensionless stress coefficient H governing the solid-fluid coupling behavior in poroelastic materials. When the phase shift between the applied cyclic loading and the corresponding fluid pressure evolution in steady-state is pronounced, the transient response is comparable in magnitude to the steady-state one and an increase in the rate of change of fluid pressure is observed immediately after loading. The transient response of fluid pressure may have a significant effect on the mechanical behavior of poroelastic materials in various fields. r
Bone undergoes a constant reconstruction process of resorption and formation called bone remodeling, so that it can endure mechanical loading. During food ingestion, masticatory muscles generate the required masticatory force. The magnitude of applied masticatory force has long been believed to be closely correlated with the shape of the jawbone. However, both the mechanism underlying this correlation and evidence of causation remain largely to be determined. Here, we established a novel mouse model of increased mastication in which mice were fed with a hard diet (HD) to elicit greater masticatory force. A novel in silico computer simulation indicated that the masticatory load onto the jawbone leads to the typical bone profile seen in the individuals with strong masticatory force, which was confirmed by in vivo micro-computed tomography (micro-CT) analyses. Mechanistically, increased mastication induced Insulin–like growth factor (IGF)-1 and suppressed sclerostin in osteocytes. IGF-1 enhanced osteoblastogenesis of the cells derived from tendon. Together, these findings indicate that the osteocytes balance the cytokine expression upon the mechanical loading of increased mastication, in order to enhance bone formation. This bone formation leads to morphological change in the jawbone, so that the bone adapts to the mechanical environment to which it is exposed.
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