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

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Jin Dai, Sheng Zhou, Qiting Ge, Jinzhong Qin, Dongyang Chen, Zhihong Xu, Dongquan Shi, Jianxin Li, Huangxian Ju, Yi Cao, Minghao Zheng, Chao Jun Li, Xiang Gao, Huajian Teng, Qing Jiang
• Journal: Journal of orthopaedic surgery and research (J Orthop Surg Res) Vol. 13 Issue 1 Pg. 118 (May 21 2018) ISSN: 1749-799X [Electronic] England
• PMID: 29784003 (Publication Type: Journal Article)

Chemical References

• GSK1210151A
• Heterocyclic Compounds, 4 or More Rings

Topics

• Aged
• Animals
• Cartilage, Articular (drug effects, metabolism)
• Cells, Cultured
• Chondrocytes (drug effects, metabolism)
• Heterocyclic Compounds, 4 or More Rings (pharmacology, therapeutic use)
• Humans
• Knee Joint (drug effects, metabolism, pathology)
• Male
• Mice
• Mice, 129 Strain
• Middle Aged
• Osteoarthritis, Knee (drug therapy, metabolism, pathology)