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...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2021-01-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-020-80244-x |
| _version_ | 1819200234942627840 |
|---|---|
| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-23T03:29:00Z |
| format | Article |
| id | doaj.art-7a28cadbee7746b4b032c27613f2cde2 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-23T03:29:00Z |
| publishDate | 2021-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-7a28cadbee7746b4b032c27613f2cde22022-12-21T18:01:46ZengNature PortfolioScientific Reports2045-23222021-01-0111111510.1038/s41598-020-80244-xAdenosine A2A receptor signaling promotes FoxO associated autophagy in chondrocytesBenjamin Friedman0Carmen Corciulo1Cristina M. Castro2Bruce N. Cronstein3Department of Medicine, Division of Rheumatology, NYU School of MedicineDepartment of Medicine, Division of Translational Medicine, NYU School of MedicineDepartment of Medicine, Division of Translational Medicine, NYU School of MedicineDepartment of Medicine, Division of Rheumatology, NYU School of MedicineAbstract 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.https://doi.org/10.1038/s41598-020-80244-x |
| spellingShingle | Benjamin Friedman Carmen Corciulo Cristina M. Castro Bruce N. Cronstein Adenosine A2A receptor signaling promotes FoxO associated autophagy in chondrocytes Scientific Reports |
| title | 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_short | Adenosine A2A receptor signaling promotes FoxO associated autophagy in chondrocytes |
| title_sort | adenosine a2a receptor signaling promotes foxo associated autophagy in chondrocytes |
| url | https://doi.org/10.1038/s41598-020-80244-x |
| work_keys_str_mv | AT benjaminfriedman adenosinea2areceptorsignalingpromotesfoxoassociatedautophagyinchondrocytes AT carmencorciulo adenosinea2areceptorsignalingpromotesfoxoassociatedautophagyinchondrocytes AT cristinamcastro adenosinea2areceptorsignalingpromotesfoxoassociatedautophagyinchondrocytes AT brucencronstein adenosinea2areceptorsignalingpromotesfoxoassociatedautophagyinchondrocytes |