The A2B adenosine receptor controls a fork in the road of mesenchymal stem cell differentiation

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The A2B adenosine receptor (A2BAR) is a G‐protein coupled receptor that signals by increasing cAMP and/or activating PKC signaling. The A2BAR is expressed on mesenchymal stem cells (MSCs), which give rise to osteoblast, chondrocyte and adipocyte lineages. We recently reported that activation of the A2BAR upregulates RUNX2, an inducer of osteogenesis, and increases the differentiation of MSCs to osteoblasts. Additionally, A2BAR null mice have impaired bone formation at baseline and after injury, and increased cartilage. To investigate whether the A2BAR is regulating fate determination of the MSC, we chose to study another lineage, the chondrocyte. We considered the possibility that the A2BAR upregulating effect on RUNX2 leads to differentiation of chondrocytes by a default pathway, involving RUNX2‐mediated downregulation of Sox9. Here, we report that A2BAR activation inhibits differentiation to chondrocytes by causing the downregulation of the key transcription factor Sox9, prior to any observed effect on RUNX2 transcription. This effect is at least partially due to cAMP signaling, as direct activation of adenylyl cyclase mimics the effect. These results support the contention that A2BAR‐induced cAMP elevation influences the lineage determination of the MSC via a direct stimulatory or inhibitory effect on key regulators of the osteoblastic or chrondrocytic lineage, respectively.This work was supported, in whole or in part, by National Institutes of Health Grant HL93149