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Register a new userInvestigation of the cellular response to bone fractures: evidence for flexoelectricity
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The recent discovery of bone flexoelectricity (electrical polarization induced by strain gradient) suggests that flexoelectricity could have physiological effects in bones, and specifically near bone fractures, where flexoelectricity is theoretically highest. Here, we report a cytological study of the interaction between crack stress and bone cells. We have cultured MC3T3-E1 mouse osteoblastic cells in biomimetic microcracked hydroxyapatite substrates, differentiated into osteocytes and applied a strain gradient to the samples. The results show a strong apoptotic cellular response, whereby mechanical stimulation causes those cells near the crack to die, as indicated by live-dead and caspase staining. In addition, analysis two weeks after stimulation shows increased cell attachment and mineralization around microcracks and a higher expression of osteocalcin, an osteogenic protein known to be promoted by physical exercise. The results are consistent with flexoelectricity playing at least two different roles in bone remodelling: apoptotic trigger of the repair protocol, and electrostimulant of the bone-building activity of osteoblasts.
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To maintain bone mass during bone remodelling, coupling is required between bone resorption and bone formation. This coordination is achieved by a network of autocrine and paracrine signalling molecules between cells of the osteoclast lineage and cells of the osteoblastic lineage. Mathematical modelling of signalling between cells of both lineages can assist in the interpretation of experimental data, clarify signalling interactions and help develop a deeper understanding of complex bone diseases. In this paper, we further develop a mathematical model of bone cell interactions by Pivonka et al. (2008) to include the proliferation of precursor osteoblasts into the model. This inclusion is important to be able to account for Wnt signalling, believed to play an important role in anabolic responses of bone. We show that an increased rate of differentiation to precursor cells or an increased rate of proliferation of precursor osteoblasts themselves both result in increased bone mass. However, modelling these different processes separately enables the new model to represent recent experimental discoveries such as the role of Wnt signalling in bone biology and the recruitment of osteoblast progenitor cells by transforming growth factor beta. Finally, we illustrate the power of the new models capabilities by applying the model to prostate cancer metastasis to bone. In the bone microenvironment, prostate cancer cells are believed to release some of the same signalling molecules used to coordinate bone remodelling (i.e. Wnt and PTHrP), enabling the cancer cells to disrupt normal signalling and coordination between bone cells. This disruption can lead to either bone gain or bone loss. We demonstrate that the new computational model developed here is capable of capturing some key observations made on the evolution of the bone mass due to metastasis of prostate cancer to the bone microenvironment
Bone is a biomaterial undergoing continuous renewal. The renewal process is known as bone remodelling and is operated by bone-resorbing cells (osteoclasts) and bone-forming cells (osteoblasts). Both biochemical and biomechanical regulatory mechanisms have been identified in the interaction between osteoclasts and osteoblasts. Here we focus on an additional and poorly understood potential regulatory mechanism of bone cells, that involves the morphology of the microstructure of bone. Bone cells can only remove and replace bone at a bone surface. However, the microscopic availability of bone surface depends in turn on the ever-changing bone microstructure. The importance of this geometrical dependence is unknown and difficult to quantify experimentally. Therefore, we develop a sophisticated mathematical model of bone cell interactions that takes into account biochemical, biomechanical and geometrical regulations. We then investigate numerically the influence of bone surface availability in bone remodelling within a representative bone tissue sample. The interdependence between the bone cells activity, which modifies the bone microstructure, and changes in the microscopic bone surface availability, which in turn influences bone cell development and activity, is implemented using a remarkable experimental relationship between bone specific surface and bone porosity. Our model suggests that geometrical regulation of the activation of new remodelling events could have a significant effect on bone porosity and bone stiffness. On the other hand, geometrical regulation of late stages of osteoblast and osteoclast differentiation seems less significant. We conclude that the development of osteoporosis is probably accelerated by this geometrical regulation in cortical bone, but probably slowed down in trabecular bone.
In this paper we develop a lattice-based computational model focused on bone resorption by osteoclasts in a single cortical basic multicellular unit (BMU). Our model takes into account the interaction of osteoclasts with the bone matrix, the interaction of osteoclasts with each other, the generation of osteoclasts from a growing blood vessel, and the renewal of osteoclast nuclei by cell fusion. All these features are shown to strongly influence the geometrical properties of the developing resorption cavity including its size, shape and progression rate, and are also shown to influence the distribution, resorption pattern and trajectories of individual osteoclasts within the BMU. We demonstrate that for certain parameter combinations, resorption cavity shapes can be recovered from the computational model that closely resemble resorption cavity shapes observed from microCT imaging of human cortical bone.
Bone remodelling is carried out by `bone multicellular units (BMUs) in which active osteoclasts and active osteoblasts are spatially and temporally coupled. The refilling of new bone by osteoblasts towards the back of the BMU occurs at a rate that depends both on the number of osteoblasts and on their secretory activity. In cortical bone, a linear phenomenological relationship between matrix apposition rate (MAR) and BMU cavity radius is found experimentally. How this relationship emerges from the combination of complex, nonlinear regulations of osteoblast number and secretory activity is unknown. Here, we extend our previous mathematical model of cell development within a single BMU to investigate how osteoblast number and osteoblast secretory activity vary along the BMUs closing cone. MARs predicted by the model are compared with data from tetracycline double labelling experiments. We find that the linear phenomenological relationship observed in these experiments between MAR and BMU cavity radius holds for most of the refilling phase simulated by our model, but not near the start and end of refilling. This suggests that at a particular bone site undergoing remodelling, bone formation starts and ends rapidly. Our model also suggests that part of the observed cross-sectional variability in tetracycline data may be due to different bone sites being refilled by BMUs at different stages of their lifetime. The different stages of a BMUs lifetime depend on whether the cell populations within the BMU are still developing or have reached a quasi-steady state while travelling through bone. We find that due to their longer lifespan, active osteoblasts reach a quasi-steady distribution more slowly than active osteoclasts. We suggest that this fact may locally enlarge the Haversian canal diameter (due to a local lack of osteoblasts compared to osteoclasts) near the BMUs point of origin.
Age-related bone loss and postmenopausal osteoporosis are disorders of bone remodelling, in which less bone is reformed than resorbed. Yet, this dysregulation of bone remodelling does not occur equally in all bone regions. Loss of bone is more pronounced near and at the endocortex, leading to cortical wall thinning and medullary cavity expansion, a process sometimes referred to as trabecularisation or cancellisation. Cortical wall thinning is of primary concern in osteoporosis due to the strong deterioration of bone mechanical properties that it is associated with. In this paper, we examine the possibility that the non-uniformity of microscopic bone surface availability could explain the non-uniformity of bone loss in osteoporosis. We use a computational model of bone remodelling in which microscopic bone surface availability influences bone turnover rate and simulate the evolution of the bone volume fraction profile across the midshaft of a long bone. We find that bone loss is accelerated near the endocortical wall where the specific surface is highest. Over time, this leads to a substantial reduction of cortical wall thickness from the endosteum. The associated expansion of the medullary cavity can be made to match experimentally observed cross-sectional data from the Melbourne Femur Collection. Finally, we calculate the redistribution of the mechanical stresses in this evolving bone structure and show that mechanical load becomes critically transferred to the periosteal cortical bone.
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