Figure 6: Endogenous adenosine maintains cartilage homeostasis.

Here we provide a conceptual model of the role of adenosine production and adenosine receptor ligation in inflammation and in the pathogenesis of OA. Adenosine is generated which ligates A2AR maintaining homeostasis in cartilage after mechanical loading and other stresses. A2AR ligation exerts an anti-inflammatory and chondroprotective effect by blocking NF-κB nuclear translocation and promoting production of growth factors. During OA progression a decrease of adenosine in the extracellular space occurs due partially to IL-1β effect on ATP and adenosine transporters and the enzymes involved in ATP/ADP catabolism. Moreover, decreased mitochondrial number, observed in OA chondrocytes, contributes to diminished cellular ATP levels. Moreover, production and release of adenosine deaminase by inflammatory cells can exacerbate the progression of OA by further reduction of adenosine levels (unpublished figure created by C.C.).