title: Effects of imatinib mesylate in osteoblastogenesis.
abstract: Imatinib mesylate (IM), a tyrosine kinase inhibitor currently used in chronic myeloid leukemia (CML), may also affect the growth of other cellular systems besides CML cells. Because it has been reported that IM may affect bone tissue remodeling, we evaluated the effects of IM on osteoblastic differentiation of human bone marrow mesenchymal stem cells (hBM-MSCs). After 21 days of culture, hBM-MSCs treated with IM (1 microM) alone or osteogenic medium (OM) + IM showed changes in morphology with evidence of extracellular mineralization and increased mRNA expression of osteogenic markers, such as RUNX2, osteocalcin (OCN), and bone morphogenetic protein (BMP-2). We also observed that levels of OCN and the osteoprotegerin (OPG)/receptor activator of nuclear factor-kappa B ligand (RANKL) ratio (OPG/RANKL ratio) were increased in the surnatant of the 21-day culture with IM or OM + IM compared to controls (p<0.005). In addition, we found that in 46 serum samples collected from CML patients treated with IM for 3 to 24 months, the OPG/RANKL ratio increased after 3 and 6 months (p<0.004) returning back to the basal level after 24 months of IM treatment. In these patients, OCN levels were low at diagnosis but they increased throughout the IM treatment, approaching normal levels at 24 months of IM therapy. In summary, our data show that IM increases mRNA expression of osteogenic markers in hBM-MSCs and increases the OPG/RANKL ratio and the OCN levels both in surnatant of hBM-MSCs cultured with IM and in serum of patients treated with IM, thus indicating that IM potentially favors osteoblastogenesis.
authors.affiliation: Department of Biomedical Sciences, Division of Hematology, University of Catania, Ospedale Ferrarotto, Catania, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Tibullo
authors.forename: Cesarina
authors.initials: C
authors.lastname: Giallongo
authors.forename: Piera
authors.initials: P
authors.lastname: La Cava
authors.forename: Salvatore
authors.initials: S
authors.lastname: Berretta
authors.forename: Fabio
authors.initials: F
authors.lastname: Stagno
authors.forename: Annalisa
authors.initials: A
authors.lastname: Chiarenza
authors.forename: Concetta
authors.initials: C
authors.lastname: Conticello
authors.forename: Giuseppe A
authors.initials: GA
authors.lastname: Palumbo
authors.forename: Francesco
authors.initials: F
authors.lastname: Di Raimondo
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D001549:Benzamides; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects*; D002454:Cell Differentiation; D002478:Cells, Cultured; D006801:Humans; D000068877:Imatinib Mesylate; D007951:Leukemia, Myeloid / Q000188:drug therapy; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects; D008969:Molecular Sequence Data; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects*; D010012:Osteogenesis / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D012015:Reference Standards; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate