Prostaglandin E2 receptor (EP2): a novel target to attenuate excessive bone loss during autoimmune arthritis

• Published in: The Journal of immunology (1950) 2017-05, Vol.198 (1_Supplement), p.217-217.8
• Main Authors: Ignatowicz, Aleksandra P, Patterson, Daryllynn C, Mula, Ramanjaneya V R, Dingledine, Raymond J, Ganesh, Thota, Shashidharamurthy, Rangaiah
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.198.Supp.217.8

Prostaglandin-E2 receptors (sub type EP2) are known to be activated during various autoimmune inflammatory disorders including rheumatoid arthritis (RA) and may play an essential role in exacerbating the bone damage during RA. Recently, we have reported that EP2 antagonists inhibited pro-inflammatory cytokine responses at the transcriptional level using murine monocytic cell line and observed that EP2 antagonists attenuate the upregulation of several inflammatory mediators in vitro. It has been shown that EP2 gene deletion in mouse cultures impairs osteoclast formation. Herein we investigated the anti-osteoclastogenic activity of recently discovered EP2 antagonists using an in vitro osteoclastogenesis model using mouse monocytic cell line (RAW264.7 cells). We observed significantly increased size and number of osteoclasts by both PGE2 and butaprost (selective EP2 agonist) compared to receptor activator of nuclear factor kappa-B ligand (RANKL) alone treated cells. We did not observe significant difference in number of osteoclasts between PGE2 and butaprost. In addition, 10μM concentration of various EP2 specific antagonists (TG8-4, TG4-155 and TG6-129) inhibited RANKL-induced osteoclast formation. Western blot analysis revealed that EP2 antagonists decreased the expression of c-Fos and nuclear factor of activated T cells c1 (NFATc1), which are the master regulators of osteoclastogenesis. These data indicates the direct effect of EP2 antagonists on bone cells in preventing the severe bone damage implying EP2 receptors play a major role during osteoclast formation, thus EP receptors should be explored as a therapeutic target to blunt the excessive bone loss during arthritis.