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The Src inhibitor dasatinib accelerates the differentiation of human bone marrow-derived mesenchymal stromal cells
Hichame Id Boufker1, Laurence Lagneaux, Mehdi Najar
1Laboratoire d'Hematologie Experimentale, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
Background:
The 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.
Methods:
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 beta-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]).
Results:
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.
Conclusions:
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.
Insights
Dasatinib, a tyrosine kinase inhibitor, promotes osteoblast differentiation and bone formation while reducing osteoclastogenesis, suggesting its potential for treating bone loss conditions like osteolysis.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- The proto-oncogene Src regulates cell signaling and negatively impacts osteoblast activity, making its inhibition a target for preventing bone loss.
- Dasatinib, a dual Src/Bcr-Abl tyrosine kinase inhibitor, shows preclinical promise in solid tumors but its effect on human osteoblasts is unknown.
Purpose of the Study:
- To investigate the effects of dasatinib on the differentiation of human bone marrow-derived mesenchymal stromal cells (MSC) into osteoblasts.
- To assess dasatinib's impact on key markers of osteoblast differentiation and bone metabolism.
Main Methods:
- Human MSC were cultured with or without dasatinib in the presence of osteogenic supplements (dexamethasone, ascorbic acid, beta-glycerophosphate).
- Osteoblast differentiation was assessed by measuring extracellular matrix mineralization, alkaline phosphatase (ALP) activity, and gene expression of osteoblastic markers (RANKL, BSP, OPN).
Main Results:
- Dasatinib significantly enhanced ALP activity and calcium deposition in differentiating osteoblasts.
- It upregulated bone sialoprotein (BSP) and osteopontin (OPN) gene expression.
- Dasatinib markedly downregulated receptor activator of nuclear factor kappa B ligand (RANKL) expression, reducing the RANKL/OPG ratio.
Conclusions:
- Dasatinib exhibits a dual role: stimulating osteoblast differentiation for direct bone formation and inhibiting osteoclastogenesis via RANKL downregulation.
- These findings position dasatinib as a potential therapeutic agent for osteolysis due to its balanced effect on bone metabolism.
