Thus, the increase in osteoclast number and function observed in A 2AR knockout (A 2AR KO) mice could be from unopposed A 1R functions where, conversely, the diminished osteoclast function observed in A 1KO mice could result from enhanced A 2AR activity.Īdenosine A 2AR activation decreases wear particle-induced inflammation Histological examination of particle-exposed WT mouse calvarias demonstrated an inflammatory cell infiltration on the outside bone surface as seen with the H&E staining. In general, as noted above, it is possible that since both adenosine A 1 and A 2A receptors (as well as A 2B receptors) are expressed on osteoclast precursors and have opposing effects on osteoclast development, wherein blockade or loss of one receptor leads to an apparent increase in baseline function of the other in response to ambient adenosine concentrations. Mice lacking adenosine A 2AR have increased numbers of osteoclasts in their bones and diminished bone density. More recently, we have observed that adenosine A 2AR activation suppresses osteoclast formation in vitro. In vivo, adenosine A 1R blockade or deletion diminished bone resorption, leading to osteopetrosis (increased bone density) in knockout mice and inhibition of post-ovariectomy–induced bone loss (, ). Previous results from our laboratory demonstrated that osteoclasts express all four adenosine receptor subtypes and, moreover, that deletion or blockade of adenosine A 1R diminishes osteoclast differentiation and function in vitro. Adenosine A 2AR possess a wide variety of anti-inflammatory effects and adenosine, by targeting either A 2AR or A 3R, mediates the anti-inflammatory effects of low-dose methotrexate, the most widely used drug for rheumatoid arthritis.

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