Adenosine A _2A receptor (A2AR) activation triggers Akt signaling and enhances nuclear localization of β‐catenin in osteoblasts

Abstract

Osteoblast differentiation and proliferation are regulated by several modulators, among which are adenosine A2a receptors (A2ARs) and Wingless/Integrated‐β‐catenin pathways. Cytosolic β‐catenin stabilization promotes its nuclear translocation and transcriptional activity. In the present study, we seek to determine whether there is a connection between A2AR stimulation and cellular β‐catenin levels in osteoblasts. Osteoblast precursor cell line (MC3T3‐E1) and primary murine osteoblasts were treated with CGS21680, a highly selective A2AR agonist. We analyzed cellular content and nuclear translocation of phosphorylated (p)‐serine 552 (S552) β‐catenin in response to A2AR stimulation in MC3T3‐E1 cells, in both wild‐type and A2AR knockout (A2AKO) mice. Moreover, we measured cellular β‐catenin levels in MC3T3‐E1 cells transfected with scrambled or protein kinase B (Akt) small interfering RNA following A2AR activation. CGS21680 (1 µM) stimulated an increase in both the cellular content and nuclear translocation of p‐S552 β‐catenin after 15 min of incubation. A2AR activation had no tangible effect on the cellular β‐catenin level either in A2AKO mice or in osteoblasts with diminished Akt content. Our findings demonstrate an interaction between A2AR, β‐catenin, and Akt signaling in osteoblasts. The existence of such a crosstalk has significant repercussions in the development of novel therapeutic approaches targeting medical conditions associated with reduced bone density.—Borhani, S., Corciulo, C., Larranaga‐Vera, A., Cronstein, B. N. Adenosine A2a receptor (A2AR) activation triggers Akt signaling and enhances nuclear localization of β‐catenin in osteoblasts. FASEB J. 33, 7555–7562 (2019). http://www.fasebj.org

Adenosine A2A receptor signaling promotes FoxO associated autophagy in chondrocytes

“…With respect to possible regulation of FoxO levels, localization, and activity, although AKT is a major inhibitory regulator of FoxOs by phosphorylation at three sites, the inhibition of AKT by A2AR signaling is unlikely to explain the observed FOXO changes given the fact that A2AR actually leads to early activation of AKT observed in osteoblasts 38 , fibroblasts 39 , and recently chondrocytes 25 . Furthermore, there was an A2AR specific effect with moderately higher cytoplasmic phospho-FoxO1 and phospho-FoxO3 in mice treated with liposomal-CGS21680 compared to liposomal-adenosine, which may result from an A2AR-specific known elevation in active AKT in chondrocytes and other cell types 38,40 . Analysis of how these pathways coexist to induce homeostasis will be an interesting future topic of study.…”

Intraarticular injection of liposomal adenosine reduces cartilage damage in established murine and rat models of osteoarthritis

“…Nitrocellulose membranes were incubated overnight at 4 C with the specific primary antibody (1:1000) and, after washing, incubated with goat anti-rabbit IRDye 800 CW and goat anti-mouse IRDye 680 RD (1:5000). Membranes were scanned with Li-Cor Odyssey equipment and the intensities of the protein bands were quantified by densitometric analysis using Image Studio software version 2.0.38 (www.licor .com) 55 .…”

MiR-552-3p promotes malignant progression of gallbladder carcinoma by reactivating the Akt/β-catenin signaling pathway due to inhibition of the tumor suppressor gene RGMA

“…Activated Akt in turn activates β-catenin and prevents its degradation. This initiates nuclear translocation, which then activates transcription of a cascade of downstream proliferation and invasion-related genes (33,34). According to these previous studies, we hypothesized that miR-552-3p would affect the Wnt and cadherin pathways through inhibiting RGMA.…”