Adenosine and Adenosine Receptors in Rheumatoid Arthritis

Melissa Padovan; Fabrizio Vincenzi; Marcello Govoni; Alessandra Bortoluzzi; Pier Andrea Borea; Katia Varani


Int J Clin Rheumatol. 2013;8(1):13-25. 

In This Article

Adenosine Pathway Modulation in RA

Several studies have shown the relationship between the adenosine pathway and joint inflammation in RA in vitro and in vivo.[84] A1, A2A, A2B and A3ARs have been characterized, by using binding and functional assays, in human synoviocytes that represent key cells closely associated to articular pathologies.[92]In vitro stimulation of A2A and A3ARs has been shown to alter the cytokine network by decreasing inflammatory cytokine secretion by macrophages. Recently, a phosphorylated A2AAR agonist was demonstrated to be a potent immunosuppressant in a model of arthritis acting by an upregulation of CD73 and A2AAR expression.[113] In animal models of acute and chronic inflammation, nonselective AR antagonists reversed the anti-inflammatory effects of MTX. Furthermore, in A2A and A3ARs-deficient mice, MTX failed to suppress inflammation in the air-pouch model, thus suggesting the pivotal role of these AR subtypes in triggering an anti-inflammatory pathway in RA.[91,114] Studies on knockout animals have shown evidence that adenosine acting A2A and A3ARs mediates the anti-inflammatory effects of low-dose MTX. In adjuvant-induced arthritis in rats and in peripheral blood mononuclear cells from RA patients, MTX treatment has been shown to enhance the anti-inflammatory effects of typical A3AR agonists via an upregulation of A3AR expression. In RA patients, the overexpression of A3ARs has been directly correlated with high levels of pro-inflammatory cytokines acting via upregulation of NF-κB.[115–118] Recently, it has been proposed that synovial tissue expresses ARs and there is a relationship between MTX exposure and adenosine receptor expression within the synovium.[119] Besides, among the theories about the mechanism of action of MTX, the primary anti-inflammatory action is attributable to adenosine release. MTX increases levels of adenosine, via inhibition of amino-imidazolo-carbossi-adenosine-ribonucleoside (AICAR) transformylase enzyme. The net effect of AICAR accumulation is a rise in intracellular AMP and adenosine levels.[120]

Atherosclerosis is another interesting topic in which we can find correlations between RA and adenosine. RA patients have an increased mortality secondary to an increased atherosclerosis due to chronic inflammation and chronic steroid therapy. Adenosine pathway and MTX are involved in the atherogenesis. MTX, via adenosine, acting upon the A2AARs and A3ARs produces an increased expression of important molecules of the reverse cholesterol transport system, a basic cholesterol homeostatic mechanism.[121] There are interesting data about A2BARs and the regulation of atherosclerosis in a mice model but, certainly, we are a long way from using these agents for protection of atherogenenesis.[122] The overexpression of A3ARs in RA was directly correlated to high levels of proinflammatory cytokines acting via an upregulation of NF-κB, which is a key player in the pathogenesis of arthritis diseases.[117] In RA patients, adenosine suppressed the elevated levels of proinflammatory cytokines such as TNF-α and IL-1β.[123] Recently it has been shown that A2A and A3ARs are upregulated in untreated RA patients and in MTX-treated RA patients. Treatment with anti-TNF-α normalized A2A and A3ARs expression and functionality.[83] It has been reported that A3AR agonists prevented cartilage damage, osteoclast/osteophyte formation, bone destruction and markedly reduced pannus formation and lymphocyte formation.[124] The A3ARs was also identified as a novel anti-inflammatory target that is upregulated in RA, psoriasis and Crohn's disease, if compared with healthy subjects it is associated with an altered PI3K-PKB/Akt signaling pathway and NF-κB activation.[125] The findings showing A2AARs and A3ARs upregulation in RA patients suggest the utilization of these receptors as therapeutic targets, modulating them with specific and well-known agonists (Table 2). Clinical evidence in RA patients shows that A3AR agonist pharmacological treatment modulates an improvement in signs and symptoms.[117] In regard to A3ARs, there are data from animal models, healthy subjects (Phase I studies) and RA patients (Phase II studies). Upon oral treatment with the selective A3AR agonist named CF101 the disease was ameliorated and a marked decrease in clinical manifestations was recorded. CF101 treatment reduced inflammation, pannus formation, cartilage destruction and bone resorption and lyses.[126] In a Phase I study in healthy subjects, CF101 was found to be safe and well tolerated with a linear pharmacokinetic activity.[127] In a Phase IIa study in RA patients, CF101 oral administration twice daily for 12 weeks was shown to be safe, well tolerated and able to mediate an improvement of disease signs and symptoms, suggesting the development of these type of drugs as antirheumatic agents. Interestingly, the expression level of A3ARs at baseline was directly correlated with the high grade of efficacy, suggesting its use as a biomarker for the pharmacodynamic and therapeutic effects of this novel agent.[116,117] The anti-inflammatory effect of A3AR was also shown in fibroblast-like synoviocytes derived from synovial fluid of RA patients.[109] In particular, the effect of a novel A3AR agonist, CF502, with high human A3AR affinity and selectivity is now under investigation. CF502 induces a dose-dependent inhibitory effect on the proliferation of fibroblast-like synoviocytes via deregulation of the NF-kB signaling pathway. Furthermore, CF502 markedly suppresses the clinical and pathological manifestations of adjuvant-induced arthritis in a rat experimental model. Other data have shown that the use of A2A and A3AR agonists significantly reduces NF-κB levels and inhibits IL-1β, IL-6 and TNF-α release in mononuclear cells from peripheral blood samples of RA patients,[85] suggesting the involvement of these ARs in the modulation of inflammatory response. It has also been found that the production of metalloproteinase (MMP) 1 and 3 was inhibited by A2A or A3AR agonists in RA patients more than in healthy controls, demonstrating the direct involvement of the adenosine receptor subtypes in the mechanism regulating joint damage in RA.[85] An inverse correlation between DAS and A2AARs and A3ARs density was recently found, suggesting that an endogeneous activation of these ARs could attenuate the disease.[85] Thus, A2A and A3ARs upregulation in RA can be seen as a compensatory mechanism to better counteract the inflammatory status. The A2AARs modulation was investigated in an animal model where the administration of a homemade agonist significantly attenuated the development of arthritis and reduced the signs of the disease.[128]