Comparison of nilotinib and imatinib inhibition of FMS receptor signaling, macrophage production and osteoclastogenesis

Abstract

References

Second-generation TKI dasatinib inhibits proliferation of mesenchymal stem cells and osteoblast differentiation in vitro

“…Expression of MOZ-TIF2 in different cell lines results in depletion of CBP from PML bodies and a strong reduction in overall cellular levels of CBP protein. 3,5 Failure to detect changes in the levels of CBP transcripts indicated that this was likely to be a posttranscriptional effect (data not shown). To explore the underlying mechanism, a stable cell line (U2Os-TRex) carrying an inducible MOZ-TIF2 expression vector 5 was cultured in the presence or absence of doxycycline and treated with a range of small molecule inhibitors of protease or proteasome activities.…”

“…3,5 Failure to detect changes in the levels of CBP transcripts indicated that this was likely to be a posttranscriptional effect (data not shown). To explore the underlying mechanism, a stable cell line (U2Os-TRex) carrying an inducible MOZ-TIF2 expression vector 5 was cultured in the presence or absence of doxycycline and treated with a range of small molecule inhibitors of protease or proteasome activities. Western blot analysis on whole cell extracts revealed that, consistent with previous results, cells induced to express YFP-MOZ-TIF2 (Figure 1a; Lane 2), (but not YFP or YFP-MOZ-TIF2 DAD1 3 ), showed a strong depletion of CBP and p300 proteins (top and middle panels), in contrast to control proteins such as a-tubulin or b-actin (lower panel).…”

“…1 Previous studies have shown that MOZ-TIF2 transforms haematopoietic progenitors 2,3 and induces acute myeloid leukemia in a murine bone marrow transplant model. 2,4 MOZ-TIF2 induces widespread changes in histone acetylation, 3,5 subverting the development of haematopoietic progenitors towards leukaemia. One mechanism critical to the leukaemogenic action of MOZ-TIF2 is its association with the lysine acetyltransferases CBP and p300.…”

“…A consequence of this interaction is the strong depletion of intracellular levels of CBP and p300 via a proteasome-independent mechanism, accompanied by a loss of transcription at p53 and nuclear receptor target genes, including the RARb2 gene. 3,5 However, the mechanism by which MOZ-TIF2 promotes depletion of cellular CBP/p300 is unknown. As MOZ-TIF2 did not alter the levels of CBP mRNA as determined by qPCR experiments (data not shown), we investigated whether proteasome or specific protease activities might contribute to the downregulation of CBP/p300.…”

“…Imatinib inhibits differentiation and activity of osteoclasts in vitro and in animals through the inhibition of colony-stimulating factor 1 receptor (CSF1R), and dasatinib seems to have similar effects on osteoclasts. [4][5][6][7] The effects of imatinib on osteoblast differentiation are, however, less uniform. 7,8 Whether the second-generation TKI dasatinib influences osteoblast proliferation and differentiation in vitro has not previously been reported.…”