Modulation of endochondral ossification by MEK inhibitors PD0325901 and AZD6244 (Selumetinib)
Modulation of endochondral ossification by MEK inhibitors PD0325901 and AZD6244 (Selumetinib)
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DOI：
10.1016/j.bone.2013.11.013
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发表时间：
2014-02-01
期刊：
影响因子：
4.1
通讯作者：
Schindeler, A.
中科院分区：
文献类型：
--
作者：
El-Hoss, J.;Kolind, M.;Schindeler, A.
MEK抑制剂（MEKi）PD 0325901和AZD 6244（司美替尼）是目前正在临床研究中用于癌症治疗的药物，然而Ras-MAPK途径也是正常骨细胞分化和功能的重要介质。在这项研究中，我们研究了这些化合物对endochondrial过程中使用在体外和体内模型的影响。PD 0325901或AZD 6244处理显著增加了颅骨成骨细胞中Runx 2和碱性磷酸酶基因的表达，并减少了诱导破骨细胞培养物中的TRAP +细胞。为了测试这些药物对骨愈合的影响，C57/B16小鼠经历闭合性胫骨骨折，并以10 mg/kg/天的PD 0325901或AZD 6244处理。骨折后第10天和第21天挑选动物，分析对侧腿的骨折骨痂和股骨生长板。在骨折后第10天，MEKi治疗显著增加了软骨痂中的软骨体积（+60%PD0325901，+20%AZD 6244），并且继续治疗导致软骨重塑延迟。在生长板处，我们观察到在PD 0325901处理的小鼠中肥大区的高度相对于增殖区增加了+78%。破骨细胞表面在生长板的末端和MEKi治疗的动物的骨折骨痂内均显著减少。在关节软骨细胞培养物中检查MEKi对编码软骨基质蛋白和分解代谢酶的基因的机械作用。PD 0325901或AZD 6244导致基质蛋白表达（Col 2a 1和Acan）增加，分解代谢因子（Mmp 13和Adamts-5）表达减少。总之，这些数据支持MEKi治疗可以影响软骨细胞肥大、基质再吸收和骨折愈合的假设。这些化合物还可以通过扩大生长板的肥大区和全身性地减少破骨细胞表面来影响骨结构。皇冠版权所有（C）2013由Elsevier Inc.发布。All rights reserved.
MEK inhibitors (MEKi) PD0325901 and AZD6244 (Selumetinib) are drugs currently under clinical investigation for cancer treatment, however the Ras-MAPK pathway is also an important mediator of normal bone cell differentiation and function. In this study we examined the effects of these compounds on endochondral processes using both in vitro and in vivo models. Treatment with PD0325901 or AZD6244 significantly increased Runx2 and Alkaline phosphate gene expression in calvarial osteoblasts and decreased TRAP + cells in induced osteoclast cultures. To test the effects of these drugs on bone healing, C57/Bl6 mice underwent a closed tibial fracture and were treated with PD0325901 or AZD6244 at 10 mg/kg/day. Animals were culled at day 10 and at day 21 post-fracture for analysis of the fracture callus and the femoral growth plate in the contralateral leg. MEKi treatment markedly increased cartilage volume in the soft callus at day 10 post-fracture (+ 60% PD0325901, +20% AZD6244) and continued treatment led to a delay in cartilage remodeling. At the growth plate, we observed an increase in the height of the hypertrophic zone relative to the proliferative zone of + 78% in PD0325901 treated mice. Osteoclast surface was significantly decreased both at the terminal end of the growth plate and within the fracture calluses of MEKi treated animals. The mechanistic effects of MEKi on genes encoding cartilage matrix proteins and catabolic enzymes were examined in articular chondrocyte cultures. PD0325901 or AZD6244 led to increased matrix protein expression (Col2a1 and Acan) and decreased expression of catabolic factors (Mmp13 and Adamts-5). Taken together, these data support the hypothesis that MEKi treatment can impact chondrocyte hypertrophy, matrix resorption, and fracture healing. These compounds can also affect bone architecture by expanding the hypertrophic zone of the growth plate and reducing osteoclast surface systemically. Crown Copyright (C) 2013 Published by Elsevier Inc. All rights reserved.