Prostaglandin E2 Receptor: A Novel Target Attenuates Excessive Bone Loss During Autoimmune Arthritis

Date of Award


Degree Type


Degree Name

Master of Science in Biomedical Sciences

First Advisor

Bonnie Buxton, PhD

Second Advisor

Srujana Rayalam, BVSc, MVSc. PhD

Third Advisor

Xinyu Eric Wang, PhD

Fourth Advisor

Richard White, PhD, FAHA

Fifth Advisor

Rangaiah Shashidharamurthy, PhD


In the past, several drugs have been developed to target cyclooxygenase-2 (COX2) to inhibit inflammation during various inflammatory disorders including autoimmune arthritis. Recent studies have shown that inhibition of COX-2 leads to deleterious cardiovascular side effects; thus, COX-2 inhibitors like Vioxx and Celebrex have been withdrawn from the market. Therefore, it would be interesting to identify a target downstream of COX-2, rather than blocking the entire COX-2 signaling pathway. Recent studies have indicated that a specific prostaglandin-E2 receptor, subtype EP2, promotes inflammation during several pathological conditions. Hence, we hypothesize that targeting the EP2 receptor may offer an innovative and alternative strategy to prevent/treat the development of immune-complex mediated arthritis such as rheumatoid arthritis. The goal of the project is to investigate whether the pharmacological inhibition of EP2 receptor is a useful strategy to blunt the inflammation during the development of arthritis, using recently discovered small molecular weight EP2 antagonists.

Herein, we have shown that EP2 antagonists (TG8-4, TG4-155 and TG6-129) inhibited pro-inflammatory cytokine responses at the transcriptional level using murine monocytic cell line (RAW264.7 cells) and observed that EP2 antagonists attenuate the upregulation of several inflammatory mediators in vitro. Our in vivo data suggests that EP2 antagonism attenuates the ongoing inflammation and excessive bone loss in collageninduced arthritis model. Further, EP2 antagonists significantly down-regulated the serum pro-inflammatory cytokine response compared to untreated arthritic mice. We have also investigated the anti-osteoclastogenic activity of EP2 antagonists using an in vitro osteoclastogenesis model with RAW264.7 cells. We observed significantly increased iv IGNATOWICZ 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 inhibited RANKL-induced osteoclast formation. Western blot analysis revealed that EP2 antagonists decreased the expression of cFos but not NFATc1 and NFkB, which are the master regulators of osteoclastogenesis. These data indicates the direct effect of EP2 antagonists on going inflammation and bone cells in preventing the severe bone damage implying EP2 receptors play a major role during osteoclast formation. Therefore EP2 receptors should be explored as a therapeutic target to blunt the ongoing inflammation as well as excessive bone loss during autoimmune arthritis.

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