@article{10902/32209,
year = {2012},
url = {https://hdl.handle.net/10902/32209},
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-? (PDGFR-?), 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, ?V?3 integrin and CCR1 expression.},
organization = {This work was supported by grants from the Spanish Ministry of Science and Innovation – ISCIII (PI081825); Mutua Madrilen˜ a Medical Research Foundation (AP27262008); Centro en Red of Regenerative Medicine and Cellular Therapy from Castilla y Leo´n, Consejerı´a de Sanidad JCyL – ISCIII; the Cooperative Research Thematic Network in Cancer (RTICC; RD06/0020/0006 and RD03/0020/0041); and Spanish FIS (PS09/01897). AG-G and CS are supported by the Centro en Red of Regenerative Medicine and Cellular Therapy from Castilla y Leo´n Project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript},
publisher = {PLoS One, 2012, 7(4), e34914},
title = {Dasatinib as a bone-modifying agent: anabolic and anti-resorptive effects},
author = {Garcia-Gomez, Antonio and Ocio San Miguel, Enrique María and Crusoe, Edvan and Santamaria, Carlos and Hernández-Campo, Pilar and Blanco, Juan F. and Sanchez-Guijo, Fermin M. and Hernández-Iglesias, Teresa and Briñón, Jesús G. and Fisac-Herrero, Rosa M. and Lee, Francis Y. and Pandiella, Atanasio},
}