Role and Function of A2A and A3 Adenosine Receptors in Patients with Ankylosing Spondylitis, Psoriatic Arthritis and Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are chronic inflammatory rheumatic diseases that affect joints, causing debilitating pain and disability. Adenosine receptors (ARs) play a key role in the mechanism of inflammation, and the activation of A2A and A3AR subtypes is often associated with a reduction of the inflammatory status. The aim of this study was to investigate the involvement of ARs in patients suffering from early-RA (ERA), RA, AS and PsA. Messenger RNA (mRNA) analysis and saturation binding experiments indicated an upregulation of A2A and A3ARs in lymphocytes obtained from patients when compared with healthy subjects. A2A and A3AR agonists inhibited nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activation and reduced inflammatory cytokines release, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6. Moreover, A2A and A3AR activation mediated a reduction of metalloproteinases (MMP)-1 and MMP-3. The effect of the agonists was abrogated by selective antagonists demonstrating the direct involvement of these receptor subtypes. Taken together, these data confirmed the involvement of ARs in chronic autoimmune rheumatic diseases highlighting the possibility to exploit A2A and A3ARs as therapeutic targets, with the aim to limit the inflammatory responses usually associated with RA, AS and PsA.

Signaling of the Purinergic System in the Joint

“…Adenosine exerts an indirect role of joint protection by modulating the pro-inflammatory NF-kB molecular signaling in immune cells. Increased expression of A2AR and A3R adenosine receptors has been measured in white cells of RA and in ankylosing spondylitis patients, an effect that decreased after anti TNF-alpha treatment, consistent with the known effect of TNF-alpha on the expression of adenosine A2AR via NF-kB activation (Varani et al, 2009;Varani et al, 2011;Ravani et al, 2017). Moreover, the effect of low dose, weekly methotrexate (MTX), the gold standard treatment for RA, is also mediated by increased released of adenosine and activation of A2AR and A3R.…”

A Non-imaging High Throughput Approach to Chemical Library Screening at the Unmodified Adenosine-A3 Receptor in Living Cells

“…For instance, the signaling pathways regulated by these receptors can promote angiogenesis (Headrick et al, 2013 ) and reduce inflammation (Antonioli et al, 2014 ). Within this family, the A 3 AR is a promising molecular target for the control of a range of pathological conditions including cancer (Montinaro et al, 2013 ; Nakamura et al, 2015 ; Cao et al, 2017 ; Joshaghani et al, 2017 ), inflammation (Cohen et al, 2014 ; Yoshida et al, 2017 ), autoimmune diseases (Ravani et al, 2017 ), ischaemia (Mulloy et al, 2013 ; González-Fernández et al, 2014 ; Hussain et al, 2014 ; Ohana et al, 2016 ) and chronic neuropathic pain (Little et al, 2015 ; Tosh et al, 2015 ), making it an important target for drug development (Borea et al, 2015 ). As a consequence, identifying new screening methods for discovery of novel chemical scaffolds which bind to the A 3 AR would be beneficial.…”

Baguan Therapy Is an Alternative in Treating Ankylosing Spondylitis: A Systematic Review Based on Existing Randomized Controlled Trials

“…Applying Baguan therapy on Du meridian helps to strengthen internal body Qi, warm channels, disperse cold, clear channels, stop pain, promote the circulation of blood, remove blood stasis, and balance Yin and Yang [39]. In the view of modern medicine, Baguan therapy helps to promote blood circulation of the back and joint fluid circulation in the bone and to strengthen the nutrition of the vertebral body.…”