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Abstract Number: 0706

Adenosine A2A Receptor Activation Reduces Markers of Chondrocyte Senescence and Cartilage Inflammation Associated with Osteoarthritis

Benjamin Friedman1 and Bruce Cronstein2, 1NYU Rheumatology, New York, NY, 2NYU Grossman School of Medicine, New York, NY

Meeting: ACR Convergence 2020

Keywords: cartilage, chondrocyte, Inflammation, Mesenchymal stem cells, Osteoarthritis

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Session Information

Date: Saturday, November 7, 2020

Session Title: Osteoarthritis & Joint Biology – Basic Science Poster

Session Type: Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: Osteoarthritis is an aging-associated disorder linked to dysfunctional metabolism, chronic inflammation, oxidative stress, and cellular senescence. Cellular senescence is associated with stable cell cycle arrest, resistance to apoptosis, and the senescence-associated secretory phenotype with NFkB activation and inflammation with upregulation of senescence markers p16, p21, and p53. Importantly, senescence causes chondrocyte dysfunction by disrupting local cartilage homeostasis and promoting ECM degradation.

Methods: TC28⍺2 human chondrocytes were treated with or without the A2AR agonist CGS21680 (CGS, 1µM). WB, IF, and RT-qPCR were employed to evaluate in vitro markers of senescence and inflammation. IHC staining was used to evaluate in vivo markers in mice with obesity-induced OA. A resazurin assay was used to measure cell viability.

Results: We demonstrated that the deacetylase Sirt1, which is known to enhance metabolism and reduce senescence, accumulates in the nucleus by WB within 30 minutes following A2AR stimulation in vitro (1.7±0.2 vs 1.0±0.2, p=0.021, n=3). This is supported by a decrease in the nuclear-to-cytoplasmic ratio of acetylated nuclear NFkB by IF (0.67±0.14 vs 1.0±0.2 , p=0.038, n=3, 20-30 cells per representative 40x HPF per experiment). We have previously shown that A2AR binding likely increases Sirt1 deacetylase activity on known target p53 because total cellular p53 and nuclear acetylated p53 were reduced. Interestingly, while full length p53 levels decrease with A2AR ligation, there was a concomitant increase in an anti-senescent, pro-longevity, stem-cell associated 35 kDa transcriptional splice variant d133p53 as assessed by western blot ratio of the isoform to full length p53 (3.0±0.8 vs 1.0±0.06, p=0.005, n=3-4). This increase was also clearly apparent by IF. Accordingly, TC28⍺2 chondrocyte viability was increased in vitro with A2AR activation by resazurin assay over 3 hours (1.15±0.08 vs. 1.0±0.08, p< 0.001, n=10). We evaluated p53-induced senescence in vivo by staining for target p21 in an obese mouse OA model. We observed a cytoplasmic shift in signal throughout the cartilage layers in mice treated with liposomal-CGS joint injections. Untreated mice had increased nuclear p21 most notable in the superficial cartilage layers. In concordance, preliminary in vitro experiments cells displayed a moderate A2AR-mediated reduction and cytoplasmic shift of p21 and p16 in TC28⍺2 chondrocytes.

Conclusion: These results indicate that A2AR binding decreases markers associated with chondrocyte senescence both in vitro and in vivo likely via activation of metabolic proteins Sirt1 and AMPK. Activation of A2AR demonstrates the integral link between healthy metabolism and organismal and cellular longevity and suggests that targeting metabolism can also reduce aging/senescence. This highlights the importance of studying the obesity-induced OA model in addition to other key OA models. Lastly, to our knowledge, the d133p53 p53 variant has not been identified in cartilage or chondrocytes and hence could provide further explanation for the specific mechanism of A2AR-mediated cartilage homeostasis and also further the general understanding the effect of senescence in OA.


Disclosure: B. Friedman, None; B. Cronstein, Regenosine, Inc., 4, 5, AstraZeneca, 1, 5, CanFite Biopharmaceuticals, 9, Horizon Pharmaceuticals, 9.

To cite this abstract in AMA style:

Friedman B, Cronstein B. Adenosine A2A Receptor Activation Reduces Markers of Chondrocyte Senescence and Cartilage Inflammation Associated with Osteoarthritis [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/adenosine-a2a-receptor-activation-reduces-markers-of-chondrocyte-senescence-and-cartilage-inflammation-associated-with-osteoarthritis/. Accessed July 3, 2022.
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