Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: S-110483 is our novel potent and selective EP4 receptor (EP4) antagonist. In addition to the well-known fact that EP4 antagonists have anti-inflammatory effects, it has recently been shown that the prostaglandin E2-EP4 signal is involved in osteoclastogenesis through RANKL expression in osteoblasts. Therefore, EP4 antagonists are expected to become useful DMARDs with anti-inflammatory and anti-bone destruction effects. The objective of this study is to clarify the usefulness of S-110483 as a novel DMARD, and it consists of the following experiments. (1) To evaluate the effects of S-110483 on the osteoclastogenesis and RANKL expression as well as (2) to evaluate the therapeutic potentials of S-110483 as a novel DMARD using rat arthritis models.
Methods: 1. Osteoclastogenesis: Mice bone-marrow cells were stimulated with M-CSF/RANKL and the numbers of differentiated osteoclasts were counted. 2. RANKL expression on osteoblasts: Mice preosteoblast cell line (MC3T3-E1) was stimulated with IL-1β and RANKL expression was evaluated. 3. The therapeutic effects of S-110483 and DMARDs on an adjuvant-induced arthritis (AIA) model: Rats were orally administered S-110483 or DMARDs for 25 days starting immediately after the adjuvant injection. Paw volumes were measured regularly. Twenty-five days after the adjuvant injection, rats were sacrificed and the wet weight of the thymus was measured. Furthermore, bone condition was evaluated by using X-ray and micro CT analysis. 4. Therapeutic effects of S-110483 and celecoxib on collagen-induced arthritis (CIA) model: DA rats were immunized with type-II collagen in CFA, and arthritis score and the paw volume were measured regularly. S-110483 or celecoxib was administered orally once a day from arthritis onset. Sixteen days after arthritis onset, bone condition was evaluated.
Results: 1. S-110483 (1–10 µmol/L) inhibited the osteoclastogenesis and its effect was more potent than tofacitinib and MTX. 2. S-110483 (1–10 µmol/L) also inhibited RANKL expression of osteoblast as well as DMARDs. 3. In the AIA model, anti-edema and anti-bone destruction effects of S-110483 were comparable with those of MTX (1 mg/kg), and were more potent than those of tofacitinib (10 mg/kg) and iguratimod (10 mg/kg). Furthermore, S-110483 showed the inhibitory effect on inflammation-related bone formation, unlike DMARDs, suggesting that S-110483 possessed excellent inhibitory effects on joint deformity. Interestingly, S-110483 improved thymus atrophy, an index of immunosuppression, unlike MTX and tofacitinib. 4. In the CIA model, while anti-edema effect of S-110483 was comparable to that of celecoxib (10 mg/kg), the anti-bone destruction effect of S-110483 was significantly more potent than that of celecoxib (10 mg/kg).
Conclusion: Our novel EP4 antagonist, S-110483, has not only anti-inflammatory effects but also has direct effects on osteoclasts and osteoblasts, similar to DMARDs. Furthermore, the anti-edema and anti-bone destruction effects of S-110483, without strong immunosuppressive effect, are comparable to those of DMARDs. These findings would support the excellent potential of S-110483 as a clinically useful DMARD.
To cite this abstract in AMA style:Ochiai T, Maeda T, Nagayasu-Tanaka T, Anzai J, Kato D, Morisaki Y, Ukai K, Suda M. S-110483, a Novel and Selective EP4 Receptor Antagonist with Anti-Bone Destruction Activities [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/s-110483-a-novel-and-selective-ep4-receptor-antagonist-with-anti-bone-destruction-activities/. Accessed May 19, 2019.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/s-110483-a-novel-and-selective-ep4-receptor-antagonist-with-anti-bone-destruction-activities/