Evidence for purinergic signaling pathways in human rheumatoid and osteoarthritis synovial tissue

Background Inflammatory joint destruction releases intracellular components like ATP and triggers an acidic microenvironment. Detection of ATP and ischemia by sensory neurons leads to pain sensation, but little is known about the presence of purinoceptors and regulating factors in synovial tissue. The current study investigates the presence of ATP-receptor P2X5, acid-sensing ion channel ASIC3, and ATP degrading ectonucleotidases NTPDase1 (CD39) and NTPDase2 in human rheumatoid arthritis (RA) and osteoarthritis (OA) synovial tissue. Methods H&E and immunofluorescent staining on 8 rheumatoid arthritis (2 male, 6 female) and 8 osteoarthritis specimens (1 male, 7 female) were analyzed. Results Synovitis score was significantly higher in RA compared to OA (p=0.0002*, 7.38 ± 1.30 versus 2.75 ± 1.28 points, mean±SD). ASIC3 and P2X5 as well as NTPDase1 and NTPDase2 show a very high, significant correlation in synovial tissue of RA lining and sublining layer (r>93%, double staining in 11.2-24.6% of all cells, single staining in 0.5-10%). A high correlation for NTPDase1 and NTPDase2 was observed also in OA sublining layer (r>94%, double staining in 15.2-37.6% of cells, 0.8-8.1% single staining). Conclusions ASIC3 and P2X5 together with NTPDase1 and NTPDase2 indicate a tightly regulated purinergic microenvironment in RA and OA synovial tissue. Data suggests that nucleotide turnover, including ATP breakdown and subsequent adenosine generation, modulates inflammatory and nociceptive processes and purinergic signaling pathways in synovitis.