Development of Novel Therapeutic Strategies for Rheumatoid Arthritis utilizing the Extracellular Adenosine and Signaling via Cell Surface Adenosine Receptors.

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1) Effects of Extracellular Adenosine on Human Synovial Cells2-Chloroadenosine (2-CADO), an adenosine deaminase (ADA) resistant general Adenosine (Ado) agonist, induced the apoptosis on the fibroblast-like synoviocytes (FLS) from rheumatoid arthritis (RA) patients (RA-FLS) in a dose-dependent manner. Incubation of FLS with Ado resulted in the inhibition of proliferation as early as an hour, which was time- and concentration-dependent.2) Expression of Cell-surface Adenosine Receptors on FLSRT-PCR assay revealed that RA-FLS and two human FLS lines expressed all the four Adenosine Receptors (AdoR) mRNA (A_1, A_<2A>, A_<2B> and A_3). Functional analysis using the selective AdoR agonists and antagonists revealed that cAMP-increasing A_<2B> AdoR was functionally dominant on FLS.3) Molecular Mechanisms of Adenosine-mediated Apoptosis on FLSA potent ado transporter inhibitor NBT, but the selective AdoR antagonists, suppressed the RA-FLS apoptosis bar 2-CADO.Incubation with cell-permeable cAMP analog or co-incubation of Ado with ADA inhibitor also failed to inhibit the apoptosis, while general caspase inhibitor z-VAD-fmk was capable of blocking the apoptosis. These data indicated the machinery that the exogenous 2-CADO after entering into the cells activated the caspases and induced the apoptotic cell death.4) Anti-rheumatic Effect of Adenosine Transporter Inhibitors in vivoThe results mentioned above opened the possibility of the ado transporter inhibitors as novel ant-rheumatic drugs. We have started to test this in rat adjuvant arthritis model. The preliminary results were that the systemic administration of NBT appears similarly or even more effective than methotrexate. Thus the further in vivo investigation of the anti-rheumatic effects of NBT and other nucleoside transporters will open a new therapeutic strategy of RA.