title: Effects of second-generation tyrosine kinase inhibitors towards osteogenic differentiation of human mesenchymal cells of healthy donors.
abstract: The BCR-ABL inhibitor imatinib is a standard first-line therapy for patients with chronic myeloid leukemia. However, it has been demonstrated that this long-term treatment is associated with altered bone metabolism. The mechanisms of this effect are not fully understood, but an inhibition of the platelet-derived growth factor receptor (PDGF-R) β axis has been suspected on the basis of some in vitro findings. We evaluated the osteoblastic differentiation of mesenchymal stem cells derived from bone marrow (hBM-MSCs) after in vitro treatment with dasatinib, nilotinib or bosutinib. Human bone marrow mesenchymal stem cells were induced to differentiate in osteoblastic cells by treatment with osteogenic medium with or without dasatinib, nilotinib or bosutinib. We found that the addition of dasatinib, and to a greater extend nilotinib, induced expression of osteogenic mRNA markers as compared with cultures with standard medium or osteogenic medium only. However, treatment with bosutinib did not induce an increase of osteogenic markers. In conclusion, we show that besides imatinib, other tyrosine kinase inhibitors (TKIs) such as dasatinib and nilotinib, but not bosutinib, increase osteogenic markers in hBM-MSCs. Because bosutinib differs from the other TKIs because of its low affinity to other kinases such as PDGF-R, these experiments suggest that inhibition of PDGF-R may be involved in the induction of osteoblastogenesis by TKIs.
authors.affiliation: Department of Clinical and Molecular Biomedicine, Division of Hematology, Ospedale Ferrarotto, University of Catania, Catania, Italy. d.tibullo@unict.it
authors.forename: Daniele
authors.initials: D
authors.lastname: Tibullo
authors.forename: Ignazio
authors.initials: I
authors.lastname: Barbagallo
authors.forename: Cesarina
authors.initials: C
authors.lastname: Giallongo
authors.forename: Piera
authors.initials: P
authors.lastname: La Cava
authors.forename: Antonio
authors.initials: A
authors.lastname: Branca
authors.forename: Concetta
authors.initials: C
authors.lastname: Conticello
authors.forename: Fabio
authors.initials: F
authors.lastname: Stagno
authors.forename: Annalisa
authors.initials: A
authors.lastname: Chiarenza
authors.forename: Giuseppe A
authors.initials: GA
authors.lastname: Palumbo
authors.forename: Francesco
authors.initials: F
authors.lastname: Di Raimondo
mesh_terms: D001549:Benzamides; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D053244:Osteoprotegerin / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use*; D053245:RANK Ligand / Q000378:metabolism; D014019:Tissue Donors
chemical_list: C525718:BMP2 protein, human; D001549:Benzamides; D055396:Bone Morphogenetic Protein 2; D016328:NF-kappa B; D053244:Osteoprotegerin; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases