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.
Highlights
Osteoarthritis (OA), a common degenerative joint disorder in older people, is characterized by progressive cartilage degradation, synovitis and subchondral bone remodeling, which are all associated with OA progression
Histological analyses confirmed that oral administration of 3 mg/kg KAG-308 significantly suppressed OA progression compared with the vehicle control group (Fig. 1c,d), accompanied with marked responsiveness
We showed that oral administration of KAG-308, an EP4-selective agonist, prevented the structural disease progression associated with synovial inflammation of surgically induced mouse OA
Summary
Osteoarthritis (OA), a common degenerative joint disorder in older people, is characterized by progressive cartilage degradation, synovitis and subchondral bone remodeling, which are all associated with OA progression. Various in vitro and in vivo studies recently reported novel candidate disease-modifying drugs for OA, including anti-inflammatory agents, antibodies against matrix metalloproteinases, and new pain-relieving drugs[12,13,14,15,16,17,18]. Among these OA-related molecules, several studies have shown that prostaglandin E2 (PGE2) is increased in the synovial fluid of OA patients and is mechanically regulated in cartilage[19,20,21,22,23]. We further examined the effects of KAG-308 treatment in the articular chondrocytes, fibroblast-like synoviocytes (FLS), and mesenchymal stem cells (MSC) to reveal the molecular mechanisms of action by KAG-308
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