Oral administration of EP4-selective agonist KAG-308 suppresses mouse knee osteoarthritis development through reduction of chondrocyte hypertrophy and TNF secretion
| Autor: | Sakae Tanaka, Ryota Chijimatsu, Masahiro Amakawa, Hideki Nakamoto, Fumiko Yano, Yoshihide Miyake, Hiroyuki Yamanaka, Taku Saito, Yasutaka Murahashi, Toshihiko Yamashita, Kousuke Iba, Yuji Maenohara |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Agonist medicine.medical_specialty medicine.drug_class Prostaglandin E2 receptor medicine.medical_treatment Biopsy Anti-Inflammatory Agents lcsh:Medicine Administration Oral Chondrocyte hypertrophy Cartilage metabolism Article 03 medical and health sciences Mice 0302 clinical medicine Chondrocytes Internal medicine medicine Cyclic AMP Animals Humans Prostaglandin E2 lcsh:Science 030203 arthritis & rheumatology Inflammation Multidisciplinary Molecular medicine business.industry Tumor Necrosis Factor-alpha Cartilage lcsh:R Synovial Membrane Osteoarthritis Knee Epoprostenol Disease Models Animal Protein Transport 030104 developmental biology Endocrinology medicine.anatomical_structure lcsh:Q Tumor necrosis factor alpha business Receptors Prostaglandin E EP4 Subtype medicine.drug Prostaglandin E Signal Transduction |
| Zdroj: | Scientific Reports Scientific Reports, Vol 9, Iss 1, Pp 1-13 (2019) |
| ISSN: | 2045-2322 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|