Role of Imatinib Mesylate in Osteoblastogenesis.

Imatinib mesylate (IM), a tyrosine kinase inhibitor, currently used in chronic myeloid leukaemia (CML) may also affect the growth of other cellular systems besides CML cells. It has been reported that IM may affect bone tissue remodeling mainly by an inhibitory activity on osteoclastogenesis. We therefore evaluated possible effects of IM on osteoblatic differentiation of Mesenchymal Stem Cells derived from bone marrow (BMSCs). BMSCs are multi-potent non-haematopoietic progenitor cells that differentiate into osteoblasts, adipocytes, chondrocytes, skeletal myocytes and nervous cells. Culture of normal human BMSCs were treated with osteogenic medium (OM) with or without IM 1 μM. By RT-PCR, we assessed mRNA expression of osteogenic markers such as RUNX2, osteocalcin (OCN) and osteopontin (OPN) at 7, 14, and 21 days of culture. BMSCs treated with OM and IM 1 μM showed increased levels of osteogenic markers mRNA as compared to BMSCs cultured with OM only (RUNX2 ctrl=0,37±0,02 vs OM+IM=0,79±0,06; OCN ctrl=0,36±0,04 vs OM+IM= 0,97±0,03; OPN ctrl=0,94±0,01 vs OM+IM= 1,55±0,13). We also evaluated the OCN levels, and the OPG (osteoprotegerin)/RANKL (receptor activator of nuclear factor-kappa B ligand) ratio (OPG/RANKL ratio) in the surnatant of the culture at day 21 by ELISA assays. OPG/RANKL ratio (OM alone = 55,4±0,4 vs OM+IM = 65,3±0,7; P<0,005) and OCN levels (OM alone = 1,4±0,08 ng/mL vs OM+IM= 4,02±0,21 ng/mL; P<0,005) were increased in BMSCs samples cultured with IM in comparison to control (OM alone). In addition, we examined the OPG/RANKL ratio in serum of 17 CML patients treated for at least two years with IM and we found that it was increased in comparison to normal controls (ctrl=1,0±0,2 vs patients= 3,1±2,63; P= 0,036). In summary, our data show that IM increases osteogenic markers’ mRNA expression in BMSCs and increase the OPG/RANKL ratio both in surnatant of BMSCs cultured with IM and in serum of patients treated with IM, thus indicating that IM potentially favours osteoblastogenesis.