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Bromodomain and Extra-terminal (BET) Protein Inhibitors Suppress Chondrocyte Differentiation and Restrain Bone Growth
Ningning Niu1, Rui Shao1, Guang Yan1
1From the State Key Laboratory of Cell Biology, Chinese Academy of Sciences Center for Excellence in Molecular Cell Sciences, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Abstract:
Small molecule inhibitors for bromodomain and extra-terminal (BET) proteins have recently emerged as potential therapeutic agents in clinical trials for various cancers. However, to date, it is unknown whether these inhibitors have side effects on bone structures. Here, we report that inhibition of BET bromodomain proteins may suppress chondrocyte differentiation and restrain bone growth. We generated a luciferase reporter system using the chondrogenic cell line ATDC5 in which the luciferase gene was driven by the promoter of Col2a1, an elementary collagen of the chondrocyte. The Col2a1-luciferase ATDC5 system was used for rapidly screening both activators and repressors of human collagen Col2a1 gene expression, and we found that BET bromodomain inhibitors reduce the Col2a1-luciferase. Consistent with the luciferase assay, BET inhibitors decrease the expression of Col2a1 Furthermore, we constructed a zebrafish line in which the enhanced green fluorescent protein (EGFP) expression was driven by col2a1 promoter. The transgenic (col2a1-EGFP) zebrafish line demonstrated that BET inhibitors I-BET151 and (+)-JQ1 may affect EGFP expression in zebrafish. Furthermore, we found that I-BET151 and (+)-JQ1 may affect chondrocyte differentiation in vitro and inhibit zebrafish growth in vivo Mechanistic analysis revealed that BET inhibitors influenced the depletion of RNA polymerase II from the Col2a1 promoter. Collectively, these results suggest that BET bromodomain inhibition may have side effects on skeletal bone structures.
Insights
Small molecule inhibitors targeting bromodomain and extra-terminal (BET) proteins may negatively impact bone development. Research indicates these BET inhibitors can suppress chondrocyte differentiation and hinder bone growth, suggesting potential skeletal side effects.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Small molecule inhibitors targeting bromodomain and extra-terminal (BET) proteins are under investigation as cancer therapeutics.
- The potential effects of BET inhibitors on bone structure and skeletal development remain largely unexplored.
Purpose of the Study:
- To investigate the impact of BET bromodomain inhibition on chondrocyte differentiation and bone growth.
- To determine if BET inhibitors possess side effects on skeletal tissues.
Main Methods:
- Development of a Col2a1-luciferase reporter system in ATDC5 chondrogenic cells to screen for modulators of collagen Col2a1 gene expression.
- Generation of a transgenic zebrafish line (col2a1-EGFP) to visualize the effects of BET inhibitors on chondrocyte differentiation in vivo.
- Assessment of RNA polymerase II dynamics at the Col2a1 promoter following BET inhibitor treatment.
Main Results:
- BET bromodomain inhibitors were found to reduce Col2a1-luciferase activity, indicating suppression of chondrocyte gene expression.
- Inhibition of BET proteins decreased Col2a1 expression in vitro and affected EGFP expression in transgenic zebrafish.
- BET inhibitors were observed to inhibit chondrocyte differentiation in vitro and impair zebrafish growth in vivo, linked to reduced RNA polymerase II at the Col2a1 promoter.
Conclusions:
- BET bromodomain inhibition may suppress chondrocyte differentiation and restrain bone growth.
- These findings suggest potential adverse side effects of BET inhibitors on skeletal bone structures.
- Further research is warranted to elucidate the precise mechanisms and clinical implications for bone health.
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