Mitoprotective therapy preserves chondrocyte viability and prevents cartilage degeneration in an ex vivo model of posttraumatic osteoarthritis

Delco, M.L.; Bonnevie, Edward D.; Szeto, Hazel; Bonassar, Lawrence J.; Fortier, Lisa A.

doi:10.1002/jor.23882

Cited by 40 publications

(36 citation statements)

References 67 publications

(112 reference statements)

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“…In the context of diseases outside of the musculoskeletal umbrella, mitochondrial protection and re-stabilization has emerged as a tool to halt disease progression or restore organ functionality (Eirin et al, 2014; Szeto, 2008; Szeto and Schiller, 2011). While our group has recently reported on preliminary evidence of mitochondrial protection in cartilage (Delco et al, 2018) the data from the present study indicate that mitochondrial stabilization may pose a robust therapeutic target in cartilage disease or degeneration.…”

Section: Discussionmentioning

confidence: 48%

Microscale frictional strains determine chondrocyte fate in loaded cartilage

Bonnevie

Delco

Bartell

et al. 2018

Journal of Biomechanics

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Mounting evidence suggests that altered lubricant levels within synovial fluid have acute biological consequences on chondrocyte homeostasis. While these responses have been connected to increased friction, the mechanisms behind this response remain unknown. Here, we combine a frictional bioreactor with confocal elastography and image-based cellular assays to establish the link between cartilage friction, microscale shear strain, and acute, adverse cellular responses. Our incorporation of cell-scale strain measurements reveals that elevated friction generates high shear strains localized near the tissue surface, and that these elevated strains are closely associated with mitochondrial dysfunction, apoptosis, and cell death. Collectively, our data establish two pathways by which chondrocytes negatively respond to friction: an immediate necrotic response and a longer term pathway involving mitochondrial dysfunction and apoptosis. Specifically, in the surface region, where shear strains can exceed 0.07, cells are predisposed to acute death; however, below this surface region, cells exhibit a pathway consistent with apoptosis in a manner predicted by local shear strains. These data reveal a mechanism through which cellular damage in cartilage arises from compromised lubrication and show that in addition to boundary lubricants, there are opportunities upstream of apoptosis to preserve chondrocyte health in arthritis therapy.

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Section: Discussionmentioning

confidence: 48%

Microscale frictional strains determine chondrocyte fate in loaded cartilage

Bonnevie

Delco

Bartell

et al. 2018

Journal of Biomechanics

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“…The aim of this study was to understand the relationships between adenosine signaling via the A2AR and mitochondrial function, and dynamics in chondrocytes. Mitoprotective therapies such as antioxidants, caspase inhibitors, and Szeto‐Schiller mitoprotective peptides have had promising results in experimental OA models, but little is understood about their potential roles on the reversal of chronic inflammaging in vivo. Before this publication, no other group has been able to demonstrate the mitoprotective effects on chondrocytes of a compound that has already been shown to modulate OA progression by increasing cartilage volumes in animal models …”

Section: Discussionmentioning

confidence: 99%

Adenosine A2A receptor (A2AR) stimulation enhances mitochondrial metabolism and mitigates reactive oxygen species‐mediated mitochondrial injury

Castro

Corciulo

Solesio³

et al. 2020

The FASEB Journal

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In OA chondrocytes, there is diminished mitochondrial production of ATP and diminished extracellular adenosine resulting in diminished adenosine A2A receptor (A2AR) stimulation and altered chondrocyte homeostasis which contributes to the pathogenesis of OA. We tested the hypothesis that A2AR stimulation maintains or enhances mitochondrial function in chondrocytes. The effect of A2AR signaling on mitochondrial health and function was determined in primary murine chondrocytes, a human chondrocytic cell line (T/C‐28a2), primary human chondrocytes, and a murine model of OA by transmission electron microscopy analysis, mitochondrial stress testing, confocal live imaging for mitochondrial inner membrane polarity, and immunohistochemistry. In primary murine chondrocytes from A2AR−/− null mice, which develop spontaneous OA by 16 weeks, there is mitochondrial swelling, dysfunction, and reduced mitochondrial content with increased reactive oxygen species (ROS) burden and diminished mitophagy, as compared to chondrocytes from WT animals. IL‐1‐stimulated T/C‐28a2 cells treated with an A2AR agonist had reduced ROS burden with increased mitochondrial dynamic stability and function, findings which were recapitulated in primary human chondrocytes. In an obesity‐induced OA mouse model, there was a marked increase in mitochondrial oxidized material which was markedly improved after intraarticular injections of liposomal A2AR agonist. These results are consistent with the hypothesis that A2AR ligation is mitoprotective in OA.

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“…Chen et al ( 2019 ) reported that scaffold-based delivery of EVs enhanced M2 polarization of synovial macrophages, reduced fibrocartilage formation, and effectively restored chondrocyte mitochondrial dysfunction, implying mitoprotective effects (Chen et al, 2019 ). Mitoprotection can be considered as specific antioxidative potential and has been found to prevent intracellular stress, apoptosis and catabolic processes after cartilage injury (Delco et al, 2018 ; Bartell et al, 2020 ).…”

Section: Therapeutic Application Of Msc-evs In Musculoskeletal Disordmentioning

confidence: 99%

Extracellular Vesicles in Musculoskeletal Pathologies and Regeneration

Herrmann

Diederichs

Melnik

et al. 2021

Front. Bioeng. Biotechnol.

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The incidence of musculoskeletal diseases is steadily increasing with aging of the population. In the past years, extracellular vesicles (EVs) have gained attention in musculoskeletal research. EVs have been associated with various musculoskeletal pathologies as well as suggested as treatment option. EVs play a pivotal role in communication between cells and their environment. Thereby, the EV cargo is highly dependent on their cellular origin. In this review, we summarize putative mechanisms by which EVs can contribute to musculoskeletal tissue homeostasis, regeneration and disease, in particular matrix remodeling and mineralization, pro-angiogenic effects and immunomodulatory activities. Mesenchymal stromal cells (MSCs) present the most frequently used cell source for EV generation for musculoskeletal applications, and herein we discuss how the MSC phenotype can influence the cargo and thus the regenerative potential of EVs. Induced pluripotent stem cell-derived mesenchymal progenitor cells (iMPs) may overcome current limitations of MSCs, and iMP-derived EVs are discussed as an alternative strategy. In the last part of the article, we focus on therapeutic applications of EVs and discuss both practical considerations for EV production and the current state of EV-based therapies.

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Mitoprotective therapy preserves chondrocyte viability and prevents cartilage degeneration in an ex vivo model of posttraumatic osteoarthritis

Cited by 40 publications

References 67 publications

Microscale frictional strains determine chondrocyte fate in loaded cartilage

Microscale frictional strains determine chondrocyte fate in loaded cartilage

Adenosine A2A receptor (A2AR) stimulation enhances mitochondrial metabolism and mitigates reactive oxygen species‐mediated mitochondrial injury

Extracellular Vesicles in Musculoskeletal Pathologies and Regeneration

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