Adenosine A2A receptor signaling promotes FoxO associated autophagy in chondrocytes

Abstract Autophagy, a homeostatic pathway upregulated during cellular stress, is decreased in osteoarthritic chondrocytes and this reduction in autophagy is thought to contribute to the development and progression of osteoarthritis (OA). The adenosine A2A receptor (A2AR) is a potent anti-inflammator...

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Autores principales:	Benjamin Friedman, Carmen Corciulo, Cristina M. Castro, Bruce N. Cronstein
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7a28cadbee7746b4b032c27613f2cde2
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spelling	oai:doaj.org-article:7a28cadbee7746b4b032c27613f2cde22021-12-02T15:22:58ZAdenosine A2A receptor signaling promotes FoxO associated autophagy in chondrocytes10.1038/s41598-020-80244-x2045-2322https://doaj.org/article/7a28cadbee7746b4b032c27613f2cde22021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-80244-xhttps://doaj.org/toc/2045-2322Abstract Autophagy, a homeostatic pathway upregulated during cellular stress, is decreased in osteoarthritic chondrocytes and this reduction in autophagy is thought to contribute to the development and progression of osteoarthritis (OA). The adenosine A2A receptor (A2AR) is a potent anti-inflammatory receptor and deficiency of this receptor leads to the development of OA in mice. Moreover, treatment using liposomally conjugated adenosine or a specific A2AR agonist improved joint scores significantly in both rats with post-traumatic OA (PTOA) and mice subjected to a high fat diet obesity induced OA. Importantly, A2AR ligation is beneficial for mitochondrial health and metabolism in vitro in primary and the TC28a2 human cell line. An additional set of metabolic, stress-responsive, and homeostatic mediators include the Forkhead box O transcription factors (FoxOs). Data has shown that mouse FoxO knockouts develop early OA with reduced cartilage autophagy, indicating that FoxO-induced homeostasis is important for articular cartilage. Given the apparent similarities between A2AR and FoxO signaling, we tested the hypothesis that A2AR stimulation improves cartilage function through activation of the FoxO proteins leading to increased autophagy in chondrocytes. We analyzed the signaling pathway in the human TC28a2 cell line and corroborated these findings in vivo in a metabolically relevant obesity-induced OA mouse model. We found that A2AR stimulation increases activation and nuclear localization of FoxO1 and FoxO3, promotes an increase in autophagic flux, improves metabolic function in chondrocytes, and reduces markers of apoptosis in vitro and reduced apoptosis by TUNEL assay in vivo. A2AR ligation additionally enhances in vivo activation of FoxO1 and FoxO3 with evidence of enhanced autophagic flux upon injection of the liposome-associated A2AR agonist in a mouse obesity-induced OA model. These findings offer further evidence that A2AR may be an excellent target for promoting chondrocyte and cartilage homeostasis.Benjamin FriedmanCarmen CorciuloCristina M. CastroBruce N. CronsteinNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Benjamin Friedman Carmen Corciulo Cristina M. Castro Bruce N. Cronstein Adenosine A2A receptor signaling promotes FoxO associated autophagy in chondrocytes
description	Abstract Autophagy, a homeostatic pathway upregulated during cellular stress, is decreased in osteoarthritic chondrocytes and this reduction in autophagy is thought to contribute to the development and progression of osteoarthritis (OA). The adenosine A2A receptor (A2AR) is a potent anti-inflammatory receptor and deficiency of this receptor leads to the development of OA in mice. Moreover, treatment using liposomally conjugated adenosine or a specific A2AR agonist improved joint scores significantly in both rats with post-traumatic OA (PTOA) and mice subjected to a high fat diet obesity induced OA. Importantly, A2AR ligation is beneficial for mitochondrial health and metabolism in vitro in primary and the TC28a2 human cell line. An additional set of metabolic, stress-responsive, and homeostatic mediators include the Forkhead box O transcription factors (FoxOs). Data has shown that mouse FoxO knockouts develop early OA with reduced cartilage autophagy, indicating that FoxO-induced homeostasis is important for articular cartilage. Given the apparent similarities between A2AR and FoxO signaling, we tested the hypothesis that A2AR stimulation improves cartilage function through activation of the FoxO proteins leading to increased autophagy in chondrocytes. We analyzed the signaling pathway in the human TC28a2 cell line and corroborated these findings in vivo in a metabolically relevant obesity-induced OA mouse model. We found that A2AR stimulation increases activation and nuclear localization of FoxO1 and FoxO3, promotes an increase in autophagic flux, improves metabolic function in chondrocytes, and reduces markers of apoptosis in vitro and reduced apoptosis by TUNEL assay in vivo. A2AR ligation additionally enhances in vivo activation of FoxO1 and FoxO3 with evidence of enhanced autophagic flux upon injection of the liposome-associated A2AR agonist in a mouse obesity-induced OA model. These findings offer further evidence that A2AR may be an excellent target for promoting chondrocyte and cartilage homeostasis.
format	article
author	Benjamin Friedman Carmen Corciulo Cristina M. Castro Bruce N. Cronstein
author_facet	Benjamin Friedman Carmen Corciulo Cristina M. Castro Bruce N. Cronstein
author_sort	Benjamin Friedman
title	Adenosine A2A receptor signaling promotes FoxO associated autophagy in chondrocytes
title_short	Adenosine A2A receptor signaling promotes FoxO associated autophagy in chondrocytes
title_full	Adenosine A2A receptor signaling promotes FoxO associated autophagy in chondrocytes
title_fullStr	Adenosine A2A receptor signaling promotes FoxO associated autophagy in chondrocytes
title_full_unstemmed	Adenosine A2A receptor signaling promotes FoxO associated autophagy in chondrocytes
title_sort	adenosine a2a receptor signaling promotes foxo associated autophagy in chondrocytes
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/7a28cadbee7746b4b032c27613f2cde2
work_keys_str_mv	AT benjaminfriedman adenosinea2areceptorsignalingpromotesfoxoassociatedautophagyinchondrocytes AT carmencorciulo adenosinea2areceptorsignalingpromotesfoxoassociatedautophagyinchondrocytes AT cristinamcastro adenosinea2areceptorsignalingpromotesfoxoassociatedautophagyinchondrocytes AT brucencronstein adenosinea2areceptorsignalingpromotesfoxoassociatedautophagyinchondrocytes
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Adenosine A2A receptor signaling promotes FoxO associated autophagy in chondrocytes

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