Combined MEK inhibition and BMP2 treatment promotes osteoblast differentiation and bone healing in Nf1Osx -/- mice.
Combined MEK inhibition and BMP2 treatment promotes osteoblast differentiation and bone healing in Nf1Osx -/- mice.
复制标题
DOI：
10.1002/jbmr.2316
复制
发表时间：
2015-01
影响因子：
6.2
通讯作者：
Elefteriou, Florent
中科院分区：
文献类型：
--
作者：
Ndong, Jean de la Croix;Stevens, David M.;Vignaux, Guillaume;Uppuganti, Sasidhar;Perrien, Daniel S.;Yang, Xiangli;Nyman, Jeffry S.;Harth, Eva;Elefteriou, Florent
关键词：
I 型神经纤维瘤病 (NF1) 是一种常染色体显性疾病，发病率为 1/3000，由编码 RAS/GTP 酶激活蛋白神经纤维蛋白的 NF1 基因突变引起。 NF1 儿童骨折后骨不愈合（假关节）仍然是一种具有挑战性的骨科疾病。了解神经纤维蛋白生物学的最新进展表明，NF1 假关节主要源于骨间充质谱系的缺陷和造血细胞对 TGFβ 的超敏反应。然而，用于增强这些患者骨愈合的临床相关药理学方法仍然有限。在这项研究中，我们报告了一种用于模拟 NF1 假关节的新型条件突变小鼠系的产生，其中 Nf1 可以在出生后小鼠的骨祖细胞中以诱导方式被消除，从而避免了与先前小鼠模型相关的侏儒症，其中 Nf1 在胚胎间充质细胞谱系中被消除。基于使用 Nf1flox/flox 骨髓基质细胞的离体细胞培养方法表明，Nf1 的缺失会以细胞自主的方式损害骨祖细胞分化，而与发育生长板衍生的或旁分泌/激素的影响无关。此外，体外基因表达和分化测定表明，Nf1 缺陷型骨祖细胞中的慢性 ERK 激活会削弱 BMP2 的促成骨特性，因为观察到只有 BMP2 和 MEK 抑制联合治疗才能促进 Nf1 缺陷型骨祖细胞的分化。这些发现的体内临床前相关性通过在 Nf1osx−/− 小鼠中观察到的骨愈合和愈伤组织强度的改善得到了证实，该小鼠接受 Trametinib（一种 MEK 抑制剂）和通过一种新型纳米颗粒和聚缩水甘油 (PEG) 为基础的递送方法在骨折部位局部释放的 BMP2。总的来说，这些结果为神经纤维蛋白在骨祖细胞中的细胞自主作用提供了新的证据，并为治疗 NF1 假关节的新的靶向方法提供了见解。
Neurofibromatosis type I (NF1) is an autosomal dominant disease with an incidence of 1/3000, caused by mutations in the NF1 gene, which encodes the RAS/GTPase-activating protein neurofibromin. Non-bone union following fracture (pseudarthrosis) in children with NF1 remains a challenging orthopedic condition to treat. Recent progress in understanding the biology of neurofibromin suggested that NF1 pseudarthrosis stems primarily from defects in the bone mesenchymal lineage and hypersensitivity of hematopoietic cells to TGFβ. However, clinically relevant pharmacological approaches to augment bone union in these patients remain limited. In this study, we report the generation of a novel conditional mutant mouse line used to model NF1 pseudoarthrosis, in which Nf1 can be ablated in an inducible fashion in osteoprogenitors of post-natal mice, thus circumventing the dwarfism associated with previous mouse models where Nf1 is ablated in embryonic mesenchymal cell lineages. An ex vivo-based cell culture approach based on the use of Nf1flox/flox bone marrow stromal cells showed that loss of Nf1 impairs osteoprogenitor cell differentiation in a cell-autonomous manner, independent of developmental growth plate-derived or paracrine/hormonal influences. In addition, in vitro gene expression and differentiation assays indicated that chronic ERK activation in Nf1-deficient osteoprogenitors blunts the pro-osteogenic property of BMP2, based on the observation that only combination treatment with BMP2 and MEK inhibition promoted the differentiation of Nf1-deficient osteoprogenitors. The in vivo preclinical relevance of these findings was confirmed by the improved bone healing and callus strength observed in Nf1osx−/− mice receiving Trametinib (a MEK inhibitor) and BMP2 released locally at the fracture site via a novel nanoparticle and polyglycidol (PEG)-based delivery method. Collectively, these results provide novel evidence for a cell-autonomous role of neurofibromin in osteoprogenitor cells and insights about a novel targeted approach for the treatment of NF1 pseudoarthrosis.
登录
查看更多内容
影响因子：
82.9
作者：
通讯作者：
--
DOI：
10.1302/0301-620x.93b8.25940
发表时间：
2011-08-01
影响因子：
--
作者：
Schindeler, A.;Birke, O.;Little, D. G.
通讯作者：
Little, D. G.
影响因子：
1.4
作者：
Birke, Oliver;Schindeler, Aaron;Little, David G.
通讯作者：
Little, David G.
影响因子：
3.5
作者：
Sharma, Richa;Wu, Xiaohua;Yang, Feng-Chun
通讯作者：
Yang, Feng-Chun
DOI：
10.1097/01.bsd.0000133466.97241.50
发表时间：
2004-12-01
影响因子：
--
作者：
Ramachandran, M;Tsirikos, TI;Saifuddin, A
通讯作者：
Saifuddin, A