Hyperactive Ras/MAPK signaling is critical for tibial nonunion fracture in neurofibromin-deficient mice
Hyperactive Ras/MAPK signaling is critical for tibial nonunion fracture in neurofibromin-deficient mice
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DOI：
10.1093/hmg/ddt333
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发表时间：
2013-12-01
影响因子：
3.5
通讯作者：
Yang, Feng-Chun
中科院分区：
文献类型：
--
作者：
Sharma, Richa;Wu, Xiaohua;Yang, Feng-Chun
1型神经纤维瘤病（NF 1）是一种常见的遗传性疾病，每3500人中就有1人患病。NF 1患者易出现骨骼衰弱表现，包括骨质减少/骨质疏松和长骨假关节（骨折不愈合）。已知NF 1中Ras/促分裂原活化蛋白激酶（MAPK）途径的超活化是细胞谱系（包括破骨细胞祖细胞和间充质干细胞（MSC），也称为成骨细胞祖细胞（pro-OBL））的异常增殖和分化的基础。我们目前的研究表明，超Ras/MAPK作为一个重要的途径，潜在的NF 1相关的骨折修复缺陷的发病机制。Nf 1缺陷的pro-OBL表现出Ras/MAPK过度活化。在体外引入NF 1 GT3激活相关结构域（NF 1 GAP相关结构域）足以挽救过度Ras活性并增强从具有骨骼异常（包括假关节或脊柱侧凸）的NF 1患者培养的NF 1（-/-）pro-OBL和NF 1人（h）MSC中的成骨细胞（OBL）分化。用PD 98059对促分裂原活化蛋白激酶激酶（MEK）信号传导的药理学抑制部分挽救了异常的Erk活化，同时增强了Nf 1缺陷型小鼠pro-OBL中OBL分化和OBL标志物osterix和骨钙素的表达。类似地，MEK抑制增强hMSC的OBL分化。此外，PD 98059挽救了Nf 1单倍不足的骨髓单核细胞（BMMNC）中异常的破骨细胞成熟。重要的是，MEK抑制剂显著改善了NF 1小鼠模型Col2.3Cre; Nf 1（flox/-）中的骨折愈合。总的来说，这些数据表明Ras/MAPK级联反应是与NF 1突变相关的骨丢失和假关节发病机制中的关键途径。这些研究为靶向MAPK通路改善骨量和治疗NF 1假关节提供了证据。
Neurofibromatosis type 1 (NF1) is a common genetic disorder affecting 1 in 3500 individuals. Patients with NF1 are predisposed to debilitating skeletal manifestations, including osteopenia/osteoporosis and long bone pseudarthrosis (nonunion fracture). Hyperactivation of the Ras/mitogen-activated protein kinase (MAPK) pathway in NF1 is known to underlie aberrant proliferation and differentiation in cell lineages, including osteoclast progenitors and mesenchymal stem cells (MSCs) also known as osteoblast progenitors (pro-OBLs). Our current study demonstrates the hyper Ras/MAPK as a critical pathway underlying the pathogenesis of NF1-associated fracture repair deficits. Nf1-deficient pro-OBLs exhibit Ras/MAPK hyperactivation. Introduction of the NF1 GTPase activating-related domain (NF1 GAP-related domain) in vitro is sufficient to rescue hyper Ras activity and enhance osteoblast (OBL) differentiation in Nf1(-/-) pro-OBLs and NF1 human (h) MSCs cultured from NF1 patients with skeletal abnormalities, including pseudarthrosis or scoliosis. Pharmacologic inhibition of mitogen-activated protein kinase kinase (MEK) signaling with PD98059 partially rescues aberrant Erk activation while enhancing OBL differentiation and expression of OBL markers, osterix and osteocalcin, in Nf1-deficient murine pro-OBLs. Similarly, MEK inhibition enhances OBL differentiation of hMSCs. In addition, PD98059 rescues aberrant osteoclast maturation in Nf1 haploinsufficient bone marrow mononuclear cells (BMMNCs). Importantly, MEK inhibitor significantly improves fracture healing in an NF1 murine model, Col2.3Cre;Nf1(flox/-). Collectively, these data indicate the Ras/MAPK cascade as a critical pathway in the pathogenesis of bone loss and pseudarthrosis related to NF1 mutations. These studies provide evidence for targeting the MAPK pathway to improve bone mass and treat pseudarthrosis in NF1.