The Src inhibitor dasatinib accelerates the differentiation of human bone marrow-derived mesenchymal stromal cells into osteoblasts.
The Src inhibitor dasatinib accelerates the differentiation of human bone marrow-derived mesenchymal stromal cells into osteoblasts.
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SRC抑制剂dasatinib加速了人骨骨髓衍生的间充质基质细胞分化成成骨细胞。
DOI：
10.1186/1471-2407-10-298
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发表时间：
2010-06-17
期刊：
影响因子：
3.8
通讯作者：
Journé F
中科院分区：
文献类型：
--
作者：
Id Boufker H;Lagneaux L;Najar M;Piccart M;Ghanem G;Body JJ;Journé F
原癌基因Src是一种重要的非受体蛋白酪氨酸激酶，参与控制细胞粘附、生长、迁移和分化的信号通路。它对成骨细胞活性进行负调节，因此，抑制它是防止骨质流失的潜在手段。达沙替尼是一种新型双重Src/Bcr-Abl酪氨酸激酶抑制剂，最初开发用于治疗慢性粒细胞白血病。它还在各种实体瘤的临床前研究中显示出有希望的结果。然而，其对人类成骨细胞分化的影响从未被研究过。我们评估了达沙替尼在存在或不存在地塞米松、抗坏血酸和 β-甘油磷酸 (DAG) 混合物的情况下长达 21 天对骨髓源性间充质基质细胞 (MSC) 分化为成骨细胞的影响。通过评估细胞外基质的矿化、碱性磷酸酶 (ALP) 活性和成骨细胞标志物（核因子 kappa B 配体受体激活剂 [RANKL]、骨唾液蛋白 [BSP]、骨桥蛋白 [OPN]）的表达来评估分化动力学。达沙替尼分别在7天和14天后显着增加与DAG培养的MSC中的ALP活性和钙沉积水平；它独立于 DAG 上调了 BSP 和 OPN 基因的表达；它显着下调RANKL基因和蛋白的表达（RANKL/OPG比率降低），这是刺激破骨细胞分化和活性的关键因素。我们的结果表明达沙替尼具有双重作用：(i) 刺激成骨细胞分化，导致骨形成直接增加；(ii) 下调成骨细胞的 RANKL 合成，导致间接抑制破骨细胞生成。因此，达沙替尼是一种潜在有趣的候选药物，通过其对骨代谢的双重作用来治疗骨溶解。
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. 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 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]). 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.
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DOI：
10.1083/jcb.96.3.639
发表时间：
1983-03
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ecarot-Charrier B;Glorieux FH;van der Rest M;Pereira G
通讯作者：
Pereira G
影响因子：
6.2
作者：
Clines, Gregory A.;Guise, Theresa A.
通讯作者：
Guise, Theresa A.
影响因子：
11.5
作者：
Boyce, Brendan F.;Xing, Lianping;Sawyer, Tomi K.
通讯作者：
Sawyer, Tomi K.
影响因子：
14
作者：
Coelho, MJ;Cabral, AT;Fernandes, MH
通讯作者：
Fernandes, MH
影响因子：
4.8
作者：
Chan, GK;Miao, DS;Goltzman, D
通讯作者：
Goltzman, D