title: Dasatinib as a bone-modifying agent: anabolic and anti-resorptive effects.
abstract: BACKGROUND
  Bone loss, in malignant or non-malignant diseases, is caused by increased osteoclast resorption and/or reduced osteoblast bone formation, and is commonly associated with skeletal complications. Thus, there is a need to identify new agents capable of influencing bone remodeling. We aimed to further pre-clinically evaluate the effects of dasatinib (BMS-354825), a multitargeted tyrosine kinase inhibitor, on osteoblast and osteoclast differentiation and function.
  
  
  METHODS
  For studies on osteoblasts, primary human bone marrow mensenchymal stem cells (hMSCs) together with the hMSC-TERT and the MG-63 cell lines were employed. Osteoclasts were generated from peripheral blood mononuclear cells (PBMC) of healthy volunteers. Skeletally-immature CD1 mice were used in the in vivo model.
  
  
  RESULTS
  Dasatinib inhibited the platelet derived growth factor receptor-β (PDGFR-β), c-Src and c-Kit phosphorylation in hMSC-TERT and MG-63 cell lines, which was associated with decreased cell proliferation and activation of canonical Wnt signaling. Treatment of MSCs from healthy donors, but also from multiple myeloma patients with low doses of dasatinib (2-5 nM), promoted its osteogenic differentiation and matrix mineralization. The bone anabolic effect of dasatinib was also observed in vivo by targeting endogenous osteoprogenitors, as assessed by elevated serum levels of bone formation markers, and increased trabecular microarchitecture and number of osteoblast-like cells. By in vitro exposure of hemopoietic progenitors to a similar range of dasatinib concentrations (1-2 nM), novel biological sequelae relative to inhibition of osteoclast formation and resorptive function were identified, including F-actin ring disruption, reduced levels of c-Fos and of nuclear factor of activated T cells 1 (NFATc1) in the nucleus, together with lowered cathepsin K, αVβ3 integrin and CCR1 expression.
  
  
  CONCLUSIONS
  Low dasatinib concentrations show convergent bone anabolic and reduced bone resorption effects, which suggests its potential use for the treatment of bone diseases such as osteoporosis, osteolytic bone metastasis and myeloma bone disease.
authors.affiliation: Centro de Investigación del Cáncer, IBMCC, Universidad de Salamanca-CSIC, Salamanca, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Garcia-Gomez
authors.forename: Enrique M
authors.initials: EM
authors.lastname: Ocio
authors.forename: Edvan
authors.initials: E
authors.lastname: Crusoe
authors.forename: Carlos
authors.initials: C
authors.lastname: Santamaria
authors.forename: Pilar
authors.initials: P
authors.lastname: Hernández-Campo
authors.forename: Juan F
authors.initials: JF
authors.lastname: Blanco
authors.forename: Fermin M
authors.initials: FM
authors.lastname: Sanchez-Guijo
authors.forename: Teresa
authors.initials: T
authors.lastname: Hernández-Iglesias
authors.forename: Jesús G
authors.initials: JG
authors.lastname: Briñón
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Fisac-Herrero
authors.forename: Francis Y
authors.initials: FY
authors.lastname: Lee
authors.forename: Atanasio
authors.initials: A
authors.lastname: Pandiella
authors.forename: Jesús F
authors.initials: JF
authors.lastname: San Miguel
authors.forename: Mercedes
authors.initials: M
authors.lastname: Garayoa
mesh_terms: D045930:Anabolic Agents / Q000494:pharmacology*; D000818:Animals; D016723:Bone Remodeling / Q000187:drug effects; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology; D000081247:CSK Tyrosine-Protein Kinase; D056657:Cathepsin K / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D000069439:Dasatinib; D005260:Female; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D060449:Wnt Signaling Pathway; D019061:src-Family Kinases
chemical_list: D045930:Anabolic Agents; D039302:Integrin alphaVbeta3; D050778:NFATC Transcription Factors; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; C071570:SNF1-related protein kinases; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D020797:Receptor, Platelet-Derived Growth Factor beta; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D017346:Protein Serine-Threonine Kinases; D056657:Cathepsin K; D000069439:Dasatinib