Endocrine Abstracts

Breakpoint cluster region abelson fusion oncoprotein (BCR-ABL) targeted tyrosine kinase inhibitors (TKIs) are widely used in long-term medications of hematological malignancies. Numerous clinical observations confirmed that these drugs significantly modify the physiology of bone tissue as a side effect. Currently, there are numerous contradictory results regarding the complex effects of TKIs on bone metabolism, as well as there is no clear evidence to explain them, either in the level of basic or clinical research.

The aim of the present study was to analyze the whole transcriptome differences of cultured murine osteoblasts (MC3T3E1) after imatinib or nilotinib treatment using SOLiD next generation RNA sequencing technique. Based on the cell viability test, 1 μM drug concentration and 6-day incubation period had the greatest effects on the expression profile of osteoblastic cells.

The results showed only three common up-regulated genes in the TKI-treated groups with almost the same expression activity compared to the control one. Ingenuity Pathway Analysis was applied to reveal the cellular response for the two drugs. Six and five top canonical pathways were identified from the whole transcriptome sequencing data in case of imatinib and nilotinib, respectively. GABA receptor cascade was found among the markedly upregulated signaling pathways in both of the treated groups. During the bone remodeling process, this signal transduction network is deeply involved in bone cell proliferation, differentiation and development.

In conclusion, this was the first study to observe the complete mRNA pattern of osteoblasts after selective TKI administration. These preliminary transcriptional results indicate various mechanisms of action of the examined TKIs on osteoblast function that might be due to their different chemical profiles and non-kinase target spectrum. Therefore, further investigation is required to verify the detected expression changes of the reported genes as well as to validate the biologically significant targets.