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Register a new userModeling the Effect of Blunt Impact on Mitochondrial Dysfunction in Cartilage
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Mounting evidence for the role of oxidative stress in the degeneration of articular cartilage after an injurious impact requires our modeling & simulation efforts to temporarily shift from just describing the effect of mechanical stress and inflammation on osteoarthritis (OA). The hypothesis that the injurious impact causes irreversible damage to chondrocyte mitochondria, which in turn increase their production of free radicals, affecting their energy production and their ability to rebuild the extracellular matrix, has to be modeled and the processes quantified in order to further the understanding of OA, its causes, and viable treatment options. The current article presents a calibrated model that captures the damage oxidative stress incurs on the cell viability, ATP production, and cartilage stability in a cartilage explant after a drop-tower impact. The model validates the biological hypothesis and will be used in further efforts to identify possibilities for treatment and be a part of a bigger modeling & simulation framework for the development of OA.
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Purpose: Experimental measurements of bone mineral density distributions (BMDDs) enable a determination of secondary mineralisation kinetics in bone, but the maximum degree of mineralisation and how this maximum is approached remain uncertain. We thus test computationally different hypotheses on late stages of bone mineralisation by simulating BMDDs in low turnover conditions. Materials and Methods: An established computational model of the BMDD that accounts for mineralisation and remodelling processes was extended to limit mineralisation to various maximum calcium capacities of bone. Simulated BMDDs obtained by reducing turnover rate from the reference trabecular BMDD under different assumptions on late stage mineralisation kinetics were compared with experimental BMDDs of low-turnover bone. Results: Simulations show that an abrupt stopping of mineralisation near a maximum calcium capacity induces a pile-up of minerals in the BMDD statistics that is not observed experimentally. With a smooth decrease of mineralisation rate, imposing low maximum calcium capacities helps to match peak location and width of simulated low turnover BMDDs with peak location and width of experimental BMDDs, but results in a distinctive asymmetric peak shape. No tuning of turnover rate and maximum calcium capacity was able to explain the differences found in experimental BMDDs between trabecular bone (high turnover) and femoral cortical bone (low turnover). Conclusions: Secondary mineralisation in human bone does not stop abruptly, but continues slowly up to a calcium content greater than 30 wt% Ca. The similar mineral heterogeneity seen in trabecular and femoral cortical bones at different peak locations was unexplained by turnover differences tested.
The formation of new bone involves both the deposition of bone matrix, and the formation of a network of cells embedded within the bone matrix, called osteocytes. Osteocytes derive from bone-synthesising cells (osteoblasts) that become buried in bone matrix during bone deposition. The generation of osteocytes is a complex process that remains incompletely understood. Whilst osteoblast burial determines the density of osteocytes, the expanding network of osteocytes regulates in turn osteoblast activity and osteoblast burial. In this paper, a spatiotemporal continuous model is proposed to investigate the osteoblast-to-osteocyte transition. The aims of the model are (i) to link dynamic properties of osteocyte generation with properties of the osteocyte network imprinted in bone, and (ii) to investigate Marottis hypothesis that osteocytes prompt the burial of osteoblasts when they become covered with sufficient bone matrix. Osteocyte density is assumed in the model to be generated at the moving bone surface by a combination of osteoblast density, matrix secretory rate, rate of entrapment, and curvature of the bone substrate, but is found to be determined solely by the ratio of the instantaneous burial rate and matrix secretory rate. Osteocyte density does not explicitly depend on osteoblast density nor curvature. Osteocyte apoptosis is also included to distinguish between the density of osteocyte lacuna and the density of live osteocytes. Experimental measurements of osteocyte lacuna densities are used to estimate the rate of burial of osteoblasts in bone matrix. These results suggest that: (i) burial rate decreases during osteonal infilling, and (ii) the control of osteoblast burial by osteocytes is likely to emanate as a collective signal from a large group of osteocytes, rather than from the osteocytes closest to the bone deposition front.
Measurements on embryonic epithelial tissues in a diverse range of organisms have shown that the statistics of cell neighbor numbers are universal in tissues where cell proliferation is the primary cell activity. Highly simplified non-spatial models of proliferation are claimed to accurately reproduce these statistics. Using a systematic critical analysis, we show that non-spatial models are not capable of robustly describing the universal statistics observed in proliferating epithelia, indicating strong spatial correlations between cells. Furthermore we show that spatial simulations using the Subcellular Element Model are able to robustly reproduce the universal histogram. In addition these simulations are able to unify ostensibly divergent experimental data in the literature. We also analyze cell neighbor statistics in early stages of chick embryo development in which cell behaviors other than proliferation are important. We find from experimental observation that cell neighbor statistics in the primitive streak region, where cell motility and ingression are also important, show a much broader distribution. A non-spatial Markov process model provides excellent agreement with this broader histogram indicating that cells in the primitive streak may have significantly weaker spatial correlations. These findings show that cell neighbor statistics provide a potentially useful signature of collective cell behavior.
Muscle uses Ca2+ as a messenger to control contraction and relies on ATP to maintain the intracellular Ca2+ homeostasis. Mitochondria are the major sub-cellular organelle of ATP production. With a negative inner membrane potential, mitochondria take up Ca2+ from their surroundings, a process called mitochondrial Ca2+ uptake. Under physiological conditions, Ca2+ uptake into mitochondria promotes ATP production. Excessive uptake causes mitochondrial Ca2+ overload, which activates downstream adverse responses leading to cell dysfunction. Moreover, mitochondrial Ca2+ uptake could shape spatio-temporal patterns of intracellular Ca2+ signaling. Malfunction of mitochondrial Ca2+ uptake is implicated in muscle degeneration. Unlike non-excitable cells, mitochondria in muscle cells experience dramatic changes of intracellular Ca2+ levels. Besides the sudden elevation of Ca2+ level induced by action potentials, Ca2+ transients in muscle cells can be as short as a few milliseconds during a single twitch or as long as minutes during tetanic contraction, which raises the question whether mitochondrial Ca2+ uptake is fast and big enough to shape intracellular Ca2+ signaling during excitation-contraction coupling and creates technical challenges for quantification of the dynamic changes of Ca2+ inside mitochondria. This review focuses on characterization of mitochondrial Ca2+ uptake in skeletal muscle and its role in muscle physiology and diseases.
Cell internalization of a blastomere, namely gastrulation, is a common and significant milestone during development of metazoans from worm to human, which generates multiple embryonic layers with distinct cell fates and spatial organizations. Although many molecular activities (e.g., cell polarization, asymmetrical intercellular adhesion, and apical actomyosin cortex contraction) have been revealed to facilitate this morphogenetic process, in this paper, we focus on gastrulation of the worm Caenorhabditis elegans and demonstrate that even a simple mechanical system, like a group of cells with isotropic repulsive and attractive interactions, can experience such internalization behavior spontaneously when dividing within a confined space. In principle, when the total cell number exceeds a threshold, a double-layer structure acquires lower potential energy and longer neighbor distance than the single-layer one. Besides, both mechanical analysis and simulation suggest that the cells with a large size or placed near a small-curvature boundary are easier to internalize. Last but not least, extra regulation on a limited part of cells to internalize autonomously can stabilize this process against motional noise. Our work successfully recaptures many key characteristics in worm gastrulation by mechanical modeling and provides a novel and rational interpretation on how this phenomenon emerges and is optimally programed.
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