A2A adenosine receptor stimulation regenerates cartilage in osteoarthritis animal model

Corciulo, Carmen; Castro, Cristina; Coughlin, Thomas R.; Jacob, Samson T.; Fenyö, David; Rifkin, Daniel B.; Kennedy, Oran D.; Angle, S.R.; Cronstein, Bruce N.

doi:10.1016/j.joca.2019.02.260

Cited by 2 publications

(10 citation statements)

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“…OA is a common and chronic rheumatologic, metabolic, and degenerative disease for which medical therapies are limited, expensive, and ineffective . Liposomal preparations of adenosine or the A2AR‐specific, CGS21680 have been shown to modulate OA progression by restoring cartilage volumes in established OA models of PTOA and obesity‐induced OA . The results here presented suggest that A2AR agonism also improves mitochondrial dynamics and function in inflamed human chondrocytic cells which promotes chondrocyte homeostasis, healing, and subsequent preservation of cartilage.…”

Section: Discussionmentioning

confidence: 99%

“…Mouse and rat knees were decalcified after sacrifice, removal of soft tissue, and fixation (4% ofPFA for 48 hours) in 10% of EDTA (7.4 pH) for 4 weeks. Parafilm-embedded histological sections (5 µm) were cut, mounted, and prepared for immunohistochemistry for mitochondrial markers (anti-ATPase (1/1000 dilution), anti-8-OHg (1/200 dilution)) as previously described [14]. Briefly, slides are incubated at 60°C for 30 minutes and deparaffinized by soaking in pure xylene for 10min three times.…”

Section: Histology Immunohistochemistry and Immunofluorescencementioning

confidence: 99%

“…With aging or in the setting of OA, intracellular ATP levels drop in chondrocytes leading to a reduction in ATP release and extracellular adenosine resulting in diminished endogenous A2AR stimulation and dysregulation of chondrocyte function . Application of liposomal preparations of either adenosine or the selective A2AR agonist CGS21680, abrogates development of OA in models of post‐traumatic OA (PTOA) in rats and obesity‐induced OA in mice …”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Histology Immunohistochemistry and Immunofluorescencementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…As predicted by our KEGG pathway analysis and previously published work on the A2ARKO mouse, most of the differences in gene expression could be explained by activation of transcription factors such as NF-κB and its downstream signaling elements. Among affected genes associated with pro-inflammatory and catabolic processes, SMAD3 is of particular interest since our group has demonstrated that in vitro and in vivo ligation of A2AR promotes nuclear localization of phosphorylated SMAD2/3 which is associated with maintenance of cartilage [6,7]. Increased SMAD3 expression in the null chondrocytes may, therefore, represent compensatory expression.…”

Section: Discussionmentioning

confidence: 99%

“…Application of liposomal preparations of either adenosine or the selective A2AR agonist (CGS21680) abrogates development of OA in models of post-traumatic OA (PTOA) in rats [5,6] and obesity-induced OA in mice [6,7]. Moreover, A2AR null mice develop spontaneous OA by 16 weeks [5,8].…”

Section: Introductionmentioning

confidence: 99%

Adenosine A2A receptor null chondrocyte transcriptome resembles that of human osteoarthritic chondrocytes

Castro

Corciulo

Friedman³

et al. 2021

Purinergic Signalling

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Adenosine signaling plays a critical role in the maintenance of articular cartilage and may serve as a novel therapeutic for osteoarthritis (OA), a highly prevalent and morbid disease without effective therapeutics in the current market. Mice lacking adenosine A2A receptors (A2AR) develop spontaneous OA by 16 weeks of age, a finding relevant to human OA since loss of adenosine signaling due to diminished adenosine production (NT5E deficiency) also leads to development of OA in mice and humans. To better understand the mechanism by which A2AR and adenosine generation protect from OA development, we examined differential gene expression in neonatal chondrocytes from WT and A2AR null mice. Analysis of differentially expressed genes was analyzed by KEGG pathway analysis, and oPOSSUM and the flatiron database were used to identify transcription factor binding enrichment, and tissue-specific network analyses and patterns were compared to gene expression patterns in chondrocytes from patients with OA. There was a differential expression of 2211 genes (padj<0.05). Pathway enrichment analysis revealed that pro-inflammatory changes, increased metalloprotease, reduced matrix organization, and homeostasis are upregulated in A2AR null chondrocytes. Moreover, stress responses, including autophagy and HIF-1 signaling, seem to be important drivers of OA and bear marked resemblance to the human OA transcriptome. Although A2AR null mice are born with grossly intact articular cartilage, we identify here the molecular foundations for early-onset OA in these mice, further establishing their role as models for human disease and the potential use of adenosine as a treatment for human disease.

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A2A adenosine receptor stimulation regenerates cartilage in osteoarthritis animal model

Cited by 2 publications

References 0 publications

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

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

Adenosine A2A receptor null chondrocyte transcriptome resembles that of human osteoarthritic chondrocytes

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