title: A Receptor Tyrosine Kinase Inhibitor, Dovitinib (TKI-258), Enhances BMP-2-Induced Osteoblast Differentiation In Vitro.
abstract: Dovitinib (TKI258) is a small molecule multi-kinase inhibitor currently in clinical phase I/II/III development for the treatment of various types of cancers. This drug has a safe and effective pharmacokinetic/pharmacodynamic profile. Although dovitinib can bind several kinases at nanomolar concentrations, there are no reports relating to osteoporosis or osteoblast differentiation. Herein, we investigated the effect of dovitinib on human recombinant bone morphogenetic protein (BMP)-2-induced osteoblast differentiation in a cell culture model. Dovitinib enhanced the BMP-2-induced alkaline phosphatase (ALP) induction, which is a representative marker of osteoblast differentiation. Dovitinib also stimulated the translocation of phosphorylated Smad1/5/8 into the nucleus and phosphorylation of mitogen-activated protein kinases, including ERK1/2 and p38. In addition, the mRNA expression of BMP-4, BMP-7, ALP, and OCN increased with dovitinib treatment. Our results suggest that dovitinib has a potent stimulating effect on BMP-2-induced osteoblast differentiation and this existing drug has potential for repositioning in the treatment of bone-related disorders.
authors.affiliation: Department of Biomedical Laboratory Science, School of Medicine, Eulji University, Daejeon 34824, Korea.
authors.forename: Yura
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Biomedical Laboratory Science, School of Medicine, Eulji University, Daejeon 34824, Korea.
authors.forename: Kyoung Jun
authors.initials: KJ
authors.lastname: Bae
authors.affiliation: Department of Biomedical Laboratory Science, School of Medicine, Eulji University, Daejeon 34824, Korea.
authors.forename: Hae Jung
authors.initials: HJ
authors.lastname: Chon
authors.affiliation: Laboratory of Translational Therapeutics, Korea Research Institute of Chemical Technology, Eulji University, Daejeon 34824, Korea.
authors.forename: Seong Hwan
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, School of Medicine, Eulji University, Daejeon 34824, Korea.
authors.forename: Soon Ae
authors.initials: SA
authors.lastname: Kim
authors.affiliation: Department of Biomedical Laboratory Science, School of Medicine, Eulji University, Daejeon 34824, Korea.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Kim
mesh_terms: D000469:Alkaline Phosphatase / Q000235:genetics; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D058492:Drug Repositioning; D005786:Gene Expression Regulation / Q000187:drug effects; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects*; D015363:Quinolones / Q000494:pharmacology*
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D001562:Benzimidazoles; D055396:Bone Morphogenetic Protein 2; D015363:Quinolones; D000469:Alkaline Phosphatase
keywords: ALP; BMP-2; Dovitinib; MAPK; Smad1/5/8; osteoblast differentiation