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Effects of imatinib and nilotinib on the whole transcriptome of cultured murine osteoblasts
Gyöngyi Kirschner1, Bernadett Balla1, Péter Horváth1
1First Department of Internal Medicine, Semmelweis University, 1083 Budapest, Hungary.
Abstract:
Numerous clinical observations have confirmed that breakpoint cluster region-abelson fusion oncoprotein tyrosine kinase inhibitors used in leukemia treatment alter bone physiology in a complex manner. The aim of the present study was to analyze the whole transcriptome of cultured murine osteoblasts and determine the changes following treatment with imatinib and nilotinib using Sequencing by Oligonucleotide Ligation and Detection next generation RNA sequencing. This study also aimed to identify candidate signaling pathways and network regulators by multivariate Ingenuity Pathway Analysis. Based on the right-tailed Fisher's exact test, significantly altered pathways including upstream regulators were defined for each drug. The correlation between these pathways and bone metabolism was also examined. The preliminary results suggest the two drugs have different mechanisms of action on osteoblasts, and imatinib was shown to have a greater effect on gene expression. Data also indicated the potential role of a number of genes and signaling cascades that may contribute to identifying novel targets for the treatment of metabolic bone diseases.
Insights
Leukemia drugs imatinib and nilotinib impact bone cells differently. Imatinib significantly altered gene expression in osteoblasts, suggesting distinct mechanisms and potential therapeutic targets for bone diseases.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Tyrosine kinase inhibitors (TKIs) are used in leukemia treatment.
- Clinical data suggest TKIs complexly affect bone physiology.
- Osteoblast function is critical for bone metabolism and health.
Purpose of the Study:
- To analyze the whole transcriptome of murine osteoblasts treated with imatinib and nilotinib.
- To identify signaling pathways and network regulators affected by these TKIs.
- To explore potential links between TKI-induced changes and bone metabolism.
Main Methods:
- Cultured murine osteoblasts were treated with imatinib and nilotinib.
- Next-generation RNA sequencing (Sequencing by Oligonucleotide Ligation and Detection) was employed.
- Multivariate Ingenuity Pathway Analysis identified significantly altered pathways and upstream regulators.
Main Results:
- Imatinib and nilotinib demonstrated different mechanisms of action on osteoblasts.
- Imatinib exhibited a more pronounced effect on osteoblast gene expression.
- Specific signaling pathways and gene networks were identified as significantly altered by each drug.
Conclusions:
- TKIs used in leukemia treatment have distinct effects on osteoblasts.
- Imatinib's greater impact on gene expression warrants further investigation.
- Identified pathways and genes may represent novel targets for metabolic bone disease treatment.
