Oral administration of EP4-selective agonist KAG-308 suppresses mouse knee osteoarthritis development through reduction of chondrocyte hypertrophy and TNF secretion

Yasutaka Murahashi, Fumiko Yano, Ryota Chijimatsu, Hideki Nakamoto, Yuji Maenohara, Masahiro Amakawa, Yoshihide Miyake, Hiroyuki Yamanaka, Kousuke Iba, Toshihiko Yamashita, Sakae Tanaka, Taku Saito

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

Osteoarthritis (OA) is one of the world’s most common degenerative diseases, but there is no disease-modifying treatment available. Previous studies have shown that prostaglandin E2 (PGE2) and PGE2 receptor 4 (EP4) are involved in OA pathogenesis; however, their roles are not fully understood. Here, we examined the efficacy of oral administration of KAG-308, an EP4-selective agonist, in surgically induced mouse knee OA. Cartilage degeneration and synovitis were significantly inhibited by the KAG-308 treatment. Chondrocyte hypertrophy and expression of tumor necrosis factor alpha (TNF) and matrix metalloproteinase 13 (Mmp13) in the synovium were suppressed in the KAG-308-treated mice. In cultured chondrocytes, hypertrophic differentiation was inhibited by KAG-308 and intranuclear translocation of histone deacetylase 4 (Hdac4) was enhanced. In cultured synoviocytes, lipopolysaccharide (LPS)-induced expression of TNF and Mmp13 was also suppressed by KAG-308. KAG-308 was detected in the synovium and cartilage of orally treated mice. TNF secretion from the synovia of KAG-308-treated mice was significantly lower than control mice. Thus, we conclude that oral administration of KAG-308 suppresses OA development through suppression of chondrocyte hypertrophy and synovitis. KAG-308 may be a potent candidate for OA drug development.

Original languageEnglish
Article number20329
JournalScientific reports
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2019
Externally publishedYes

ASJC Scopus subject areas

  • General

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