%0 Journal Article
%T The Src inhibitor dasatinib accelerates the differentiation of human bone marrow-derived mesenchymal stromal cells into osteoblasts
%A Hichame Id Boufker
%A Laurence Lagneaux
%A Mehdi Najar
%A Martine Piccart
%A Ghanem Ghanem
%A Jean-Jacques Body
%A Fabrice Journ¨¦
%J BMC Cancer
%D 2010
%I BioMed Central
%R 10.1186/1471-2407-10-298
%X We 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 ¦Â-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]).Dasatinib 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.Our 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.Osteoblasts originate from mesenchymal osteoprogenitor cells and play a key role in physiological bone turnover and pathological disorders including osteoporosis [1], Paget's disease [2] and tumor-induced osteolysis [3]. Osteoblast functions are dependent on their differentiation status. Indeed, immature osteoblasts regulate recruitment, differentiation and maturation of osteoclasts [4], as well as activity of osteoclasts [5]. By contrast, mature osteoblasts produce bone matrix (collagen synthesis and mineralization) [6]. Thus, the control of osteoblast differentiation is critical in the management of bone diseases.In recent years, much interest emerged for the bone marrow-
%U http://www.biomedcentral.com/1471-2407/10/298