Figure 6.

Fine-tuning control of adenosine (ADO) A_2A and A₃ receptors activation in human subcutaneous fibroblasts (HSCF) and its putative pathophysiological implications in wound healing, dermal fibrosis, and myofascial pain. Stressed HSCF release huge amounts of ATP to the extracellular medium, actions of which are rapidly terminated by NTPDase1, resulting in the formation of AMP. HSCFs exhibit high amounts of ecto-5′-nucleotidase/CD73, leading to fast dephosphorylation of AMP into ADO, which tends to accumulate in the extracellular milieu due to a very low ADO deaminase (ADA) activity in these cells. The close proximity between ecto-5′-nucleotidase/CD73 and the A_2A receptor and their parallel induction during HSCF cells maturation favor activation of the A_2A receptor by ADO generated endogenously from ATP extracellular breakdown. Thus, during normal wound closure, ADO produced by differentiated HSCF may contribute to normal collagen production and vasodilation (via A_2A receptors activation) while reducing pain sensation through stimulation of A₁ inhibitory receptors on peripheral nerve afferents. A different scenario may, however, occur due to unpredicted inosine (INO) formation as a consequence of ADA-bearing inflammatory cell infiltrates as well as in conditions exhibiting high serum ADA levels, such as fibromyalgia and chronic inflammatory states. INO, via constitutively expressed A₃ receptors, decrease HSCF growth and consequently collagen production. Thus, the novel anti-fibrotic effect of INO together with the anti-inflammatory and the anti-nociceptive properties of highly selective A₃ receptor agonists undergoing clinical trials may be useful for the treatment of dermal fibrosis and myofascial pain associated with inappropriate subcutaneous tissue remodeling. Considering that overexpression of A_2A receptors is a common feature in fibroblast malignancies (e.g., dermal fibrosis, scleroderma, radiation dermal injury), association between A₃ receptor agonists and A_2A receptor antagonists may also be proposed. On the other hand, re-equilibration of ADO/INO concentration ratio using ADA blockers may be helpful to promote immune suppression and nociception relief in myofascial pain conditions with or without A₁ and/or A₃ receptor agonists. See text for additional information. Illustration used elements from Servier Medical Art (http://smart.servier.com).