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Mitoprotective therapy prevents rapid, strain-dependent mitochondrial dysfunction after articular cartilage injury.

ABSTRACT: Posttraumatic osteoarthritis (PTOA) involves the mechanical and biological deterioration of articular cartilage that occurs following joint injury. PTOA is a growing problem in health care due to the lack of effective therapies combined with an aging population with high activity levels. Recently, acute mitochondrial dysfunction and altered cellular respiration have been associated with cartilage degeneration after injury. This finding is particularly important because recently developed mitoprotective drugs, including SS peptides, can preserve mitochondrial structure and function after acute injury in other tissues. It is not known, however, if cartilage injury induces rapid structural changes in mitochondria, to what degree mitochondrial dysfunction in cartilage depends on the mechanics of injury or the time frame over which such dysfunction develops. Similarly, it is unknown if SS-peptide treatment can preserve mitochondrial structure and function after cartilage injury. Here, we combined fast camera elastography, longitudinal fluorescence assays, and computer vision techniques to track the fates of thousands of individual cells. Our results show that impact induces mechanically dependent mitochondrial depolarization within a few minutes after injury. Electron microscopy revealed that impact causes rapid structural changes in mitochondria that are related to reduced mitochondrial function, namely, fission and loss of cristae structure. We found that SS-peptide treatment prior to impact protects the mitochondrial structure and preserves mitochondrial function at levels comparable with that of unimpacted control samples. Overall, this study reveals the vital role of mitochondria in mediating cartilage's peracute (within minutes) response to traumatic injury and demonstrates mitoprotection as a promising therapeutic strategy for injury-induced cartilage damage.

SUBMITTER: Bartell LR

PROVIDER: S-EPMC7225065 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.

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Mitoprotective therapy prevents rapid, strain-dependent mitochondrial dysfunction after articular cartilage injury.

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