Bi-directional regulation of cartilage metabolism by inhibiting BET proteins-analysis of the effect of I-BET151 on human chondrocytes and murine joints

• Published in: Journal of orthopaedic surgery and research Vol. 13; no. 1; p. 118
• Main Authors: Dai, Jin, Zhou, Sheng, Ge, Qiting, Qin, Jinzhong, Chen, Dongyang, Xu, Zhihong, Shi, Dongquan, Li, Jianxin, Ju, Huangxian, Cao, Yi, Zheng, Minghao, Li, Chao Jun, Gao, Xiang, Teng, Huajian, Jiang, Qing
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 21.05.2018; BioMed Central; BMC
• Subjects: Aged; Animals; Bet protein; Brd; Care and treatment; Cartilage; Cartilage (articular); Cartilage anabolism; Cartilage cells; Cartilage diseases; Cartilage, Articular - drug effects; Cartilage, Articular - metabolism; Cells, Cultured; Chondrocytes; Chondrocytes - drug effects; Chondrocytes - metabolism; Chondrodyte; Cytokines; Development and progression; Drug dosages; Enzymes; Fibroblasts; Heterocyclic Compounds, 4 or More Rings - pharmacology; Heterocyclic Compounds, 4 or More Rings - therapeutic use; Histopathology; Humans; IL-1β; Inflammation; Joint diseases; Kinases; Knee; Knee Joint - drug effects; Knee Joint - metabolism; Knee Joint - pathology; Male; Matrix-degrading enzymes; Mice; Mice, 129 Strain; Middle Aged; Orthopedics; Osteoarthritis; Osteoarthritis, Knee - drug therapy; Osteoarthritis, Knee - metabolism; Osteoarthritis, Knee - pathology; Proteins; R&D; Research & development; Rheumatoid arthritis; Risk factors; Sox9 protein; Stem cells; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Chondrodyte; Cartilage anabolism; Brd; Osteoarthritis; Matrix-degrading enzymes
• ISSN: 1749-799X; 1749-799X
• DOI: 10.1186/s13018-018-0797-y

Proinflammatory cytokines, which can upregulate the expression of matrix-degrading enzymes in chondrocytes, play important roles in the development of osteoarthritis. And a BET protein inhibitor, I-BET151, has been shown to exert an anti-inflammatory effect by repressing the BET protein-mediated expression of inflammatory genes. Our objective is to investigate the effect of I-BET151 on a surgical mouse model of osteoarthritis (OA) and human chondrocytes. We first treated a surgical mouse model of OA with I-BET151 once per day and evaluated the knee joints at 6 and 8 weeks after treatment. We then pretreated the human chondrocytes with I-BET151 prior to treatment with IL-1β or TNF-α and checked the expression and activity of the matrix-degrading enzyme genes. We also checked the expression of ACAN, COL2A1, and SOX9. We demonstrated that I-BET151 could prevent articular cartilage damage in the surgical mouse model of OA at an earlier time after treatment, but not at a later time after treatment. I-BET151 could robustly suppress the IL-1β- and TNF-α-induced expression and activity of several matrix-degrading enzymes in human chondrocytes. I-BET151 could also suppress the expression of ACAN, COL2A1, and SOX9. Our findings suggested that inhibiting BET proteins could exert a repression effect on both of chondrocyte anabolism and catabolism, and the effect of BET protein inhibitor on surgical mouse model of OA needs further evaluation.