Dasatinib as a bone-modifying agent: anabolic and anti-resorptive effects.
Dasatinib as a bone-modifying agent: anabolic and anti-resorptive effects.
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DOI：
10.1371/journal.pone.0034914
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Garayoa M
中科院分区：
文献类型：
--
作者：
Garcia-Gomez A;Ocio EM;Crusoe E;Santamaria C;Hernández-Campo P;Blanco JF;Sanchez-Guijo FM;Hernández-Iglesias T;Briñón JG;Fisac-Herrero RM;Lee FY;Pandiella A;San Miguel JF;Garayoa M
在恶性或非恶性疾病中，骨质流失是由破骨细胞吸收增加和/或成骨细胞成骨减少引起的，通常与骨骼并发症有关。因此，有必要确定能够影响骨重塑的新药物。我们旨在进一步临床前评估多靶点酪氨酸激酶抑制剂达沙替尼（BMS-354825）对成骨细胞和破骨细胞分化和功能的影响。成骨细胞的研究采用人骨髓间充质干细胞（hMSCs）、hMSC-TERT和MG-63细胞系。用健康志愿者外周血单个核细胞（PBMC）制备破骨细胞。体内模型采用骨骼未成熟的CD1小鼠。达沙替尼抑制hMSC-TERT和MG-63细胞系血小板衍生生长因子受体-β (PDGFR-β)、c-Src和c-Kit磷酸化，这与细胞增殖减少和典型Wnt信号激活有关。低剂量达沙替尼（2-5 nM）治疗来自健康供体的MSCs，以及来自多发性骨髓瘤患者的MSCs，促进了其成骨分化和基质矿化。通过提高血清骨形成标志物水平、增加小梁微结构和成骨细胞样细胞数量来评估，达沙替尼的骨合成代谢作用也通过靶向内源性骨祖细胞在体内观察到。通过将造血祖细胞体外暴露于相似的达沙替尼浓度范围（1 - 2 nM），发现了与抑制破骨细胞形成和吸收功能相关的新的生物学后遗症，包括F-actin环断裂，细胞核中c-Fos和活化T细胞核因子1 （NFATc1）水平降低，以及组织蛋白酶K、αVβ3整合素和CCR1表达降低。低浓度达沙替尼显示出骨合成代谢趋同和骨吸收减少的作用，这表明它可能用于治疗骨质疏松症、溶骨性骨转移和骨髓瘤等骨病。
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. 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. Dasatinib inhibited the platelet derived growth factor receptor-β (PDGFR-β), 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, αVβ3 integrin and CCR1 expression. Low dasatinib concentrations show convergent bone anabolic and reduced bone resorption effects, which suggests its potential use for the treatment of bone diseases such as osteoporosis, osteolytic bone metastasis and myeloma bone disease.
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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。
影响因子：
3.8
作者：
Id Boufker H;Lagneaux L;Najar M;Piccart M;Ghanem G;Body JJ;Journé F
通讯作者：
Journé F
影响因子：
4.1
作者：
Fowler, Jessica A.;Edwards, Claire M.;Croucher, Peter I.
通讯作者：
Croucher, Peter I.
影响因子：
11.4
作者：
Corre, J.;Mahtouk, K.;Bourin, P.
通讯作者：
Bourin, P.
影响因子：
4.8
作者：
HOCK, JM;CANALIS, E
通讯作者：
CANALIS, E
影响因子：
20.3
作者：
Han, JH;Choi, SJ;Roodman, GD
通讯作者：
Roodman, GD