Oral administration of EP4-selective agonist KAG-308 suppresses mouse knee osteoarthritis development through reduction of chondrocyte hypertrophy and TNF secretion
Oral administration of EP4-selective agonist KAG-308 suppresses mouse knee osteoarthritis development through reduction of chondrocyte hypertrophy and TNF secretion
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DOI：
10.1038/s41598-019-56861-6
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发表时间：
2019-12
影响因子：
4.6
通讯作者：
Yasutaka Murahashi;Fumiko Yano;Ryota Chijimatsu;Hideki Nakamoto;Y. Maenohara;M. Amakawa;Yoshihide Miyake;Hiroyuki Yamanaka;K. Iba;T. Yamashita;Sakae Tanaka;Taku Saito
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文献类型：
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作者：
Yasutaka Murahashi;Fumiko Yano;Ryota Chijimatsu;Hideki Nakamoto;Y. Maenohara;M. Amakawa;Yoshihide Miyake;Hiroyuki Yamanaka;K. Iba;T. Yamashita;Sakae Tanaka;Taku Saito
骨关节炎（OA）是世界上最常见的退行性疾病之一，但目前还没有改善疾病的治疗方法。以往的研究表明，前列腺素E2（PGE 2）和前列腺素E2受体4（EP 4）参与OA的发病机制，但他们的作用并不完全清楚。在这里，我们研究了口服给予KAG-308（一种EP 4选择性激动剂）对手术诱导的小鼠膝关节OA的疗效。KAG-308治疗显著抑制了软骨变性和滑膜炎。软骨细胞肥大和滑膜中肿瘤坏死因子α（TNF）和基质金属蛋白酶13（Mmp 13）的表达在KAG-308处理的小鼠中受到抑制。在培养的软骨细胞中，肥大分化被KAG-308抑制，组蛋白去乙酰化酶4（Hdac 4）的核内易位被增强。在培养的滑膜细胞中，脂多糖（LPS）诱导的TNF和Mmp 13的表达也被KAG-308抑制。在经口处理的小鼠的滑膜和软骨中检测到KAG-308。从KAG-308处理的小鼠的滑膜分泌的TNF显著低于对照小鼠。因此，我们得出结论，口服施用KAG-308通过抑制软骨细胞肥大和滑膜炎来抑制OA发展。KAG-308可能是OA药物开发的有效候选物。
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.