Induction of SHP2 deficiency in chondrocytes causes severe scoliosis and kyphosis in mice.
Induction of SHP2 deficiency in chondrocytes causes severe scoliosis and kyphosis in mice.
复制标题
软骨细胞中SHP2缺乏症的诱导会导致小鼠的严重脊柱侧弯和脑脊柱。
DOI：
10.1097/brs.0b013e3182a3d370
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发表时间：
2013-10-01
期刊：
影响因子：
3
通讯作者：
Kamiya N
中科院分区：
文献类型：
--
作者：
Kim HK;Aruwajoye O;Sucato D;Richards BS;Feng GS;Chen D;King PD;Kamiya N
利用基因工程技术建立了幼年性脊柱侧弯出生后骨骼发育阶段的动物模型。目的探讨靶向软骨细胞SHP2(Src Homology-2)缺失对幼年发育期小鼠脊柱侧弯发生的影响。青少年特发性脊柱侧弯可导致进行性严重脊柱畸形。导致这种情况的病理生理学和分子机制在很大程度上是未知的。在这里，我们调查了软骨细胞中SHP2缺乏作为青少年脊柱侧弯发展的一个潜在原因的作用。产生了软骨细胞中SHP2基因可诱导缺失的基因工程小鼠。从4周龄的小鼠开始，软骨细胞中的SHP2功能在幼年生长期失活。放射学、显微CT和组织学评估用于分析脊柱的变化。当SHP2缺乏症在幼年期被诱导时，在SHP2缺乏症开始的2周内就会发展为进行性的脊柱后凸畸形(胸椎前凸和胸腰椎后凸)。三维显微CT分析证实脊柱后凸畸形伴有脊柱旋转畸形和骨赘形成。组织学分析显示椎体生长板软骨组织紊乱。有趣的是，当SHP2在青春期到成人期被破坏时，没有出现脊柱畸形。在骨骼成熟过程中，Shp2在正常脊柱发育中起着重要作用。软骨细胞特异性的SHP2缺失在幼年阶段会导致脊柱后凸畸形。这一新的小鼠模型将有助于进一步研究软骨细胞中SHP2缺乏作为导致青少年脊柱侧弯发生机制的作用。
Genetic engineering techniques were used to develop an animal model of juvenile scoliosis during a postnatal skeletal-growth stage. To investigate the effect of targeted SHP2 (Src homology-2)-deficiency in chondrocytes on the development of scoliosis during a juvenile growth stage in mice. Juvenile idiopathic scoliosis can lead to progressive severe spinal deformity. The pathophysiology and molecular mechanisms responsible for this are largely unknown. Here, we investigated the role of SHP2-deficiency in chondrocytes as a potential cause of juvenile scoliosis development. Genetically engineered mice with inducible deletion of SHP2 in chondrocytes were generated. The SHP2 function in chondrocytes was inactivated during a juvenile growth stage from the mouse age of 4-weeks. Radiographic, micro-CT, and histological assessments were used to analyze spinal changes. When SHP2-deficiency was induced during the juvenile stage, a progressive kyphoscoliotic deformity (thoracic lordosis and thoracolumbar kyphoscoliosis) developed within 2 weeks of the initiation of SHP2-deficiency. The 3-dimensional micro-CT analysis confirmed the kyphoscoliotic deformity with a rotational deformity of the spine and osteophyte formation. The histological analysis revealed disorganization of the vertebral growth plate cartilage. Interestingly, when SHP2 was disrupted during the adolescent to adult stages, no spinal deformity developed. SHP2 plays an important role in normal spine development during skeletal maturation. Chondrocyte-specific deletion of SHP2 at a juvenile stage produced a kyphoscoliotic deformity. This new mouse model will be useful for future investigations of the role of SHP2-deficiency in chondrocytes as a mechanism leading to the development of juvenile scoliosis.