Dataset Information

Strain-dependent oxidant release in articular cartilage originates from mitochondria.

ABSTRACT: Mechanical loading is essential for articular cartilage homeostasis and plays a central role in the cartilage pathology, yet the mechanotransduction processes that underlie these effects remain unclear. Previously, we showed that lethal amounts of reactive oxygen species (ROS) were liberated from the mitochondria in response to mechanical insult and that chondrocyte deformation may be a source of ROS. To this end, we hypothesized that mechanically induced mitochondrial ROS is related to the magnitude of cartilage deformation. To test this, we measured axial tissue strains in cartilage explants subjected to semi-confined compressive stresses of 0, 0.05, 0.1, 0.25, 0.5, or 1.0 MPa. The presence of ROS was then determined by confocal imaging with dihydroethidium, an oxidant sensitive fluorescent probe. Our results indicated that ROS levels increased linearly relative to the magnitude of axial strains (r(2) = 0.87, p < 0.05), and significant cell death was observed at strains >40%. By contrast, hydrostatic stress, which causes minimal tissue strain, had no significant effect. Cell-permeable superoxide dismutase mimetic Mn(III)tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride significantly decreased ROS levels at 0.5 and 0.25 MPa. Electron transport chain inhibitor, rotenone, and cytoskeletal inhibitor, cytochalasin B, significantly decreased ROS levels at 0.25 MPa. Our findings strongly suggest that ROS and mitochondrial oxidants contribute to cartilage mechanobiology.

SUBMITTER: Brouillette MJ

PROVIDER: S-EPMC3940668 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Strain-dependent oxidant release in articular cartilage originates from mitochondria.

Brouillette M J MJ Ramakrishnan P S PS Wagner V M VM Sauter E E EE Journot B J BJ McKinley T O TO Martin J A JA

Biomechanics and modeling in mechanobiology 20130730 3

Mechanical loading is essential for articular cartilage homeostasis and plays a central role in the cartilage pathology, yet the mechanotransduction processes that underlie these effects remain unclear. Previously, we showed that lethal amounts of reactive oxygen species (ROS) were liberated from the mitochondria in response to mechanical insult and that chondrocyte deformation may be a source of ROS. To this end, we hypothesized that mechanically induced mitochondrial ROS is related to the magn ...[more]

PMID: 23896937

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Project description:Mechanical damage is central to both initiation and progression of osteoarthritis (OA). However, specific causal links between mechanics and cartilage damage are incompletely understood, which results in an inability to predict failure. The lack of understanding is primarily due to the difficulty in simultaneously resolving the high rates and small length scales relevant to the problem and in correlating such measurements to the resulting fissures. This study leveraged microscopy and high-speed imaging to resolve mechanics on the previously unexamined time and length scales of interest in cartilage damage, and used those mechanics to develop predictive models. The specific objectives of this study were to: first, quantify bulk and local mechanics during impact-induced fissuring; second, develop predictive models of fissuring based on bulk mechanics and local strain; and third, evaluate the accuracy of these models in predicting fissures. To achieve these three objectives, bovine tibial cartilage was impacted using a custom spring-loaded device mounted on an inverted microscope. The occurrence of fissures was modulated by varying impact energy. For the first objective, during impact, deformation was captured at 10,000 frames per second and bulk and local mechanics were analyzed. For the second objective, data from samples impacted with a 1.2 mm diameter rod were fit to logistic regression functions, creating models of fissure probability based on bulk and local mechanics. Finally, for the third objective, data from samples impacted with a 0.8 mm diameter rod were used to test the accuracy of model predictions. This study provides a direct comparison between bulk and local mechanical thresholds for the prediction of fissures in cartilage samples, and demonstrates that local mechanics provide more accurate predictions of local failure than bulk mechanics provide. Bulk mechanics were accurate predictors of fissure for the entire sample cohort, but poor predictors of fissure for individual samples. Local strain fields were highly heterogeneous and significant differences were determined between fissured and intact samples, indicating the presence of damage thresholds. In particular, first principal strain rate and maximum shear strain were the best predictors of local failure, as determined by concordance statistics. These data provide an important step in establishing causal links between local mechanics and cartilage damage; ultimately, data such as these can be used to link macro- and micro-scale mechanics and thereby predict mechanically mediated disease on a subject-specific basis.

Dataset Information

Strain-dependent oxidant release in articular cartilage originates from mitochondria.

Publications

Strain-dependent oxidant release in articular cartilage originates from mitochondria.

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