Obeticholic Acid Derivative, T-2054 Suppresses Osteoarthritis via Inhibiting NF-κB-Signaling Pathway

• Published in: International journal of molecular sciences Vol. 22; no. 8; p. 3807
• Main Authors: Guo, Dandan, He, Liming, Gao, Yaoxin, Jin, Chenxu, Lin, Haizhen, Zhang, Li, Wang, Liting, Zhou, Ying, Yao, Jie, Duan, Yixin, Yang, Renzheng, Qiu, Wenwei, Jiang, Wenzheng
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 07-04-2021; MDPI
• Subjects: Acids; Animal models; Animals; Anti-inflammatory agents; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Apoptosis; Arthritis; ATDC5 chondrocytes; Biomarkers; Biomedical materials; Cartilage; Cartilage - drug effects; Cartilage - metabolism; Cartilage - pathology; Cartilage diseases; Cell Line; Cell proliferation; Cell Survival - drug effects; Chemical compounds; Chenodeoxycholic Acid - analogs & derivatives; Chenodeoxycholic Acid - chemistry; Chenodeoxycholic Acid - pharmacology; Chenodeoxycholic Acid - therapeutic use; Chondrocytes; Cytokines; Cytokines - metabolism; Cytotoxicity; Degeneration; Disease Models, Animal; Drugs; Extracellular matrix; Gene expression; Gene Expression Regulation - drug effects; Inflammation; Inflammation Mediators - metabolism; Interleukin 6; Interleukin 8; Lipopolysaccharides; Lipopolysaccharides - adverse effects; Liver diseases; Male; Mice; mRNA; NF-kappa B - metabolism; NF-κB protein; NF-κB-signaling; Nitric oxide; Nitric Oxide - biosynthesis; Osteoarthritis; Osteoarthritis - drug therapy; Osteoarthritis - etiology; Osteoarthritis - metabolism; Osteoarthritis - pathology; Pain; Pharmacology; Phosphorylation; RAW 264.7 cell line; RAW 264.7 Cells; Signal transduction; Signal Transduction - drug effects; T-2054; Toxicity; Tumor necrosis factor-α; NF-κB-signaling; RAW 264.7 cell line; osteoarthritis; T-2054; ATDC5 chondrocytes
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22083807

Osteoarthritis (OA), a degenerative joint disorder, has been reported as the most common cause of disability worldwide. The production of inflammatory cytokines is the main factor in OA. Previous studies have been reported that obeticholic acid (OCA) and OCA derivatives inhibited the release of proinflammatory cytokines in acute liver failure, but they have not been studied in the progression of OA. In our study, we screened our small synthetic library of OCA derivatives and found T-2054 had anti-inflammatory properties. Meanwhile, the proliferation of RAW 264.7 cells and ATDC5 cells were not affected by T-2054. T-2054 treatment significantly relieved the release of NO, as well as mRNA and protein expression levels of inflammatory cytokines (IL-6, IL-8 and TNF-α) in LPS-induced RAW 264.7 cells. Moreover, T-2054 promoted extracellular matrix (ECM) synthesis in TNF-α-treated ATDC5 chondrocytes. Moreover, T-2054 could relieve the infiltration of inflammatory cells and degeneration of the cartilage matrix and decrease the levels of serum IL-6, IL-8 and TNF-α in DMM-induced C57BL/6 mice models. At the same time, T-2054 showed no obvious toxicity to mice. Mechanistically, T-2054 decreased the extent of p-p65 expression in LPS-induced RAW 264.7 cells and TNF-α-treated ATDC5 chondrocytes. In summary, we showed for the first time that T-2054 effectively reduced the release of inflammatory mediators, as well as promoted extracellular matrix (ECM) synthesis via the NF-κB-signaling pathway. Our findings support the potential use of T-2054 as an effective therapeutic agent for the treatment of OA.