Potential of a Novel Chemical Compound Targeting Matrix Metalloprotease-13 for Early Osteoarthritis: An In Vitro Study

• Published in: International journal of molecular sciences 2022-02, Vol.23 (5), p.2681
• Main Authors: Inagaki, Junko, Nakano, Airi, Hatipoglu, Omer Faruk, Ooka, Yuka, Tani, Yurina, Miki, Akane, Ikemura, Kentaro, Opoku, Gabriel, Ando, Ryosuke, Kodama, Shintaro, Ohtsuki, Takashi, Yamaji, Hirosuke, Yamamoto, Shusei, Katsuyama, Eri, Watanabe, Shogo, Hirohata, Satoshi
• Format: Article
• Language: English
• Subjects: ADAM protein; Arthritis; Attenuation; Betamethasone; Biomedical materials; Cartilage; Cartilage diseases; Cartilage, Articular - metabolism; Cells, Cultured; Chemical compounds; Chondrocytes - metabolism; Chondrosarcoma; Collagen; Collagenase 3; Cytokines; Cytotoxicity; Drug development; Drug dosages; Enzymes; Gene expression; Humans; IL-1β; Interleukin-1beta - metabolism; Matrix metalloproteinase; Matrix Metalloproteinase 13 - genetics; Matrix Metalloproteinase 13 - metabolism; Matrix metalloproteinases; Matrix Metalloproteinases - metabolism; Nonsteroidal anti-inflammatory drugs; Osteoarthritis; Osteoarthritis - metabolism; Phosphorylation; Protein expression; Proteins; RNA, Messenger - metabolism; Signal transduction; Thrombospondin
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23052681

Osteoarthritis is a progressive disease characterized by cartilage destruction in the joints. Matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) play key roles in osteoarthritis progression. In this study, we screened a chemical compound library to identify new drug candidates that target MMP and ADAMTS using a cytokine-stimulated OUMS-27 chondrosarcoma cells. By screening PCR-based mRNA expression, we selected 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide as a potential candidate. We found that 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide attenuated IL-1β-induced MMP13 mRNA expression in a dose-dependent manner, without causing serious cytotoxicity. Signaling pathway analysis revealed that 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide attenuated ERK- and p-38-phosphorylation as well as JNK phosphorylation. We then examined the additive effect of 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide in combination with low-dose betamethasone on IL-1β-stimulated cells. Combined treatment with 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide and betamethasone significantly attenuated MMP13 and ADAMTS9 mRNA expression. In conclusion, we identified a potential compound of interest that may help attenuate matrix-degrading enzymes in the early osteoarthritis-affected joints.