The Src inhibitor dasatinib accelerates the differentiation of human bone marrow-derived mesenchymal stromal cells into osteoblasts

BMC Cancer

Research Article

Martine Piccart¹  Mehdi Najar²  Laurence Lagneaux²  Hichame Id Boufker³  Ghanem Ghanem⁴  Fabrice Journé⁴  Jean-Jacques Body⁵ 

[1] Clinique d'Oncologie Médicale, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium;Laboratoire d'Hématologie Expérimentale, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium;Laboratoire d'Hématologie Expérimentale, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium;Laboratoire d'Oncologie et de Chirurgie Expérimentale, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium;Laboratoire d'Oncologie et de Chirurgie Expérimentale, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium;Service de Médecine, CHU Brugmann, Université Libre de Bruxelles, Brussels, Belgium;

关键词: Chronic Myeloid Leukemia;    Osteogenic Differentiation;    Dasatinib;    Mesenchymal Stromal Cell;    Stimulate Osteoblast Differentiation;   

DOI  :  10.1186/1471-2407-10-298

 received in 2009-08-20, accepted in 2010-06-17,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundThe proto-oncogene Src is an important non-receptor protein tyrosine kinase involved in signaling pathways that control cell adhesion, growth, migration and differentiation. It negatively regulates osteoblast activity, and, as such, its inhibition is a potential means to prevent bone loss. Dasatinib is a new dual Src/Bcr-Abl tyrosine kinase inhibitor initially developed for the treatment of chronic myeloid leukemia. It has also shown promising results in preclinical studies in various solid tumors. However, its effects on the differentiation of human osteoblasts have never been examined.MethodsWe evaluated the effects of dasatinib on bone marrow-derived mesenchymal stromal cells (MSC) differentiation into osteoblasts, in the presence or absence of a mixture of dexamethasone, ascorbic acid and β-glycerophosphate (DAG) for up to 21 days. The differentiation kinetics was assessed by evaluating mineralization of the extracellular matrix, alkaline phosphatase (ALP) activity, and expression of osteoblastic markers (receptor activator of nuclear factor kappa B ligand [RANKL], bone sialoprotein [BSP], osteopontin [OPN]).ResultsDasatinib significantly increased the activity of ALP and the level of calcium deposition in MSC cultured with DAG after, respectively, 7 and 14 days; it upregulated the expression of BSP and OPN genes independently of DAG; and it markedly downregulated the expression of RANKL gene and protein (decrease in RANKL/OPG ratio), the key factor that stimulates osteoclast differentiation and activity.ConclusionsOur results suggest a dual role for dasatinib in both (i) stimulating osteoblast differentiation leading to a direct increase in bone formation, and (ii) downregulating RANKL synthesis by osteoblasts leading to an indirect inhibition of osteoclastogenesis. Thus, dasatinib is a potentially interesting candidate drug for the treatment of osteolysis through its dual effect on bone metabolism.

【 授权许可】

Unknown   
© Id Boufker et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.