Potential of a Novel Chemical Compound Targeting Matrix Metalloprotease-13 for Early Osteoarthritis: An In Vitro Study.
Junko InagakiAiri NakanoOmer Faruk HatipogluYuka OokaYurina TaniAkane MikiKentaro IkemuraGabriel OpokuRyosuke AndoShintaro KodamaTakashi OhtsukiHirosuke YamajiShusei YamamotoEri KatsuyamaShogo WatanabeSatoshi HirohataPublished in: International journal of molecular sciences (2022)
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.
Keyphrases
- induced apoptosis
- signaling pathway
- rheumatoid arthritis
- low dose
- cell cycle arrest
- pi k akt
- knee osteoarthritis
- endoplasmic reticulum stress
- cell migration
- oxidative stress
- human health
- cell proliferation
- multiple sclerosis
- epithelial mesenchymal transition
- single cell
- high dose
- drug delivery
- protein kinase
- drug induced
- risk assessment
- diabetic rats
- combination therapy