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Oral administration of EP4-selective agonist KAG-308 suppresses mouse knee osteoarthritis development through reduction of chondrocyte hypertrophy and TNF secretion
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 (PGE(2)) and PGE2 receptor 4 (EP(4)) are involved in OA pathogenesis; however, their roles are not fully understood. H...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937271/ https://www.ncbi.nlm.nih.gov/pubmed/31889132 http://dx.doi.org/10.1038/s41598-019-56861-6 |
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author | Murahashi, Yasutaka Yano, Fumiko Chijimatsu, Ryota Nakamoto, Hideki Maenohara, Yuji Amakawa, Masahiro Miyake, Yoshihide Yamanaka, Hiroyuki Iba, Kousuke Yamashita, Toshihiko Tanaka, Sakae Saito, Taku |
author_facet | Murahashi, Yasutaka Yano, Fumiko Chijimatsu, Ryota Nakamoto, Hideki Maenohara, Yuji Amakawa, Masahiro Miyake, Yoshihide Yamanaka, Hiroyuki Iba, Kousuke Yamashita, Toshihiko Tanaka, Sakae Saito, Taku |
author_sort | Murahashi, Yasutaka |
collection | PubMed |
description | 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 (PGE(2)) and PGE2 receptor 4 (EP(4)) are involved in OA pathogenesis; however, their roles are not fully understood. Here, we examined the efficacy of oral administration of KAG-308, an EP(4)-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. |
format | Online Article Text |
id | pubmed-6937271 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-69372712020-01-06 Oral administration of EP4-selective agonist KAG-308 suppresses mouse knee osteoarthritis development through reduction of chondrocyte hypertrophy and TNF secretion Murahashi, Yasutaka Yano, Fumiko Chijimatsu, Ryota Nakamoto, Hideki Maenohara, Yuji Amakawa, Masahiro Miyake, Yoshihide Yamanaka, Hiroyuki Iba, Kousuke Yamashita, Toshihiko Tanaka, Sakae Saito, Taku Sci Rep Article 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 (PGE(2)) and PGE2 receptor 4 (EP(4)) are involved in OA pathogenesis; however, their roles are not fully understood. Here, we examined the efficacy of oral administration of KAG-308, an EP(4)-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. Nature Publishing Group UK 2019-12-30 /pmc/articles/PMC6937271/ /pubmed/31889132 http://dx.doi.org/10.1038/s41598-019-56861-6 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Murahashi, Yasutaka Yano, Fumiko Chijimatsu, Ryota Nakamoto, Hideki Maenohara, Yuji Amakawa, Masahiro Miyake, Yoshihide Yamanaka, Hiroyuki Iba, Kousuke Yamashita, Toshihiko Tanaka, Sakae Saito, Taku Oral administration of EP4-selective agonist KAG-308 suppresses mouse knee osteoarthritis development through reduction of chondrocyte hypertrophy and TNF secretion |
title | Oral administration of EP4-selective agonist KAG-308 suppresses mouse knee osteoarthritis development through reduction of chondrocyte hypertrophy and TNF secretion |
title_full | Oral administration of EP4-selective agonist KAG-308 suppresses mouse knee osteoarthritis development through reduction of chondrocyte hypertrophy and TNF secretion |
title_fullStr | Oral administration of EP4-selective agonist KAG-308 suppresses mouse knee osteoarthritis development through reduction of chondrocyte hypertrophy and TNF secretion |
title_full_unstemmed | Oral administration of EP4-selective agonist KAG-308 suppresses mouse knee osteoarthritis development through reduction of chondrocyte hypertrophy and TNF secretion |
title_short | Oral administration of EP4-selective agonist KAG-308 suppresses mouse knee osteoarthritis development through reduction of chondrocyte hypertrophy and TNF secretion |
title_sort | oral administration of ep4-selective agonist kag-308 suppresses mouse knee osteoarthritis development through reduction of chondrocyte hypertrophy and tnf secretion |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937271/ https://www.ncbi.nlm.nih.gov/pubmed/31889132 http://dx.doi.org/10.1038/s41598-019-56861-6 |
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