The Role of Adenosine in Bone: An Emerging Concept

The role of ATP in the differentiation and function of bone cells has been well-described, with particular focus on the P2X7 and the P2Y2 receptors. ATP, however, can be rapidly broken down by a series of enzymatic reactions to adenosine and adenosine binds to another family of receptors, the P1 or A receptors. We recently provided the first evidence of adenosine secretion from osteoprogenitor cells, and show that such cells express adenosine receptors and the enzymes that are involved in the synthesis (CD73) and metabolism (adenosine deaminase) of adenosine. Exogenously added adenosine stimulated IL-6 and alkaline phosphatase secretion, but inhibited osteoprotegerin expression, and mineralization of cells in culture suggesting its possible involvement in osteoblastgenesis and osteoblast function. Others have recently shown that 1) adenosine receptor agonists, but not antagonists, protected osteoblasts against H2O2-mediated cell death, 2) extracellular ATP and adenosine play important roles in regulating osteoblast differentiation in human valve interstitial cells 3) the A3 adenosine receptor is downregulated in osteoarthritis and 4) agonism of the A3 receptor inhibited bone destruction in an animal model of arthritis. Collectively, these findings suggest that targeting adenosine pathways may be of value in diseases where there is abnormal bone activity.