A mouse model of osteochondromagenesis from clonal inactivation of Ext1 in chondrocytes
A mouse model of osteochondromagenesis from clonal inactivation of Ext1 in chondrocytes
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DOI：
10.1073/pnas.0910875107
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发表时间：
2010-02-02
影响因子：
11.1
通讯作者：
Sheffield, Val C.
中科院分区：
文献类型：
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作者：
Jones, Kevin B.;Piombo, Virginia;Sheffield, Val C.
我们报道了多发性骨软骨瘤（MO）的小鼠模型，这是一种人类常染色体显性疾病，也被称为多发性遗传性外生骨病（MHE或HME），其特征是软骨内骨的外凸形成软骨覆盖的骨骼生长。这些骨软骨瘤的发病机制尚不清楚。Ext1或Ext2的杂合小鼠，模拟导致MO的人类基因型，偶尔会在肋骨上形成孤立的骨软骨瘤样结构[Lin et .（2000）中华生物医学工程杂志，24(2):299-311；Stickens et . (2005) Development 132(22):5055-5068]。我们没有模拟种系基因型，而是模拟了体细胞杂合性缺失（LOH）的嵌合组织基因型，方法是通过头对头loxP位点有条件地灭活Ext1，并暂时控制软骨细胞中的cree -重组酶。这些小鼠忠实地再现了多发性干骺端骨软骨瘤的人类表型。我们还证实了Ext1在骨软骨瘤软骨细胞中的纯合子破坏及其在增生的骨骺软骨细胞中的起源。这些结果解释了先前的建模失败与发育调节细胞类型中体细胞LOH的必要性。
We report a mouse model of multiple osteochondromas (MO), an autosomal dominant disease in humans, also known as multiple hereditary exostoses (MHE or HME) and characterized by the formation of cartilage-capped osseous growths projecting from the metaphyses of endochondral bones. The pathogenesis of these osteochondromas has remained unclear. Mice heterozygous for Ext1 or Ext2, modeling the human genotypes that cause MO, occasionally develop solitary osteochondroma-like structures on ribs [Lin et al. (2000) Dev Biol 224(2): 299-311; Stickens et al. (2005) Development 132(22):5055-5068]. Rather than model the germ-line genotype, we modeled the chimeric tissue genotype of somatic loss of heterozygosity (LOH), by conditionally inactivating Ext1 via head-to-head loxP sites and temporally controlled Cre-recombinase in chondrocytes. These mice faithfully recapitulate the human phenotype of multiple metaphyseal osteochondromas. We also confirm homozygous disruption of Ext1 in osteochondroma chondrocytes and their origin in proliferating physeal chondrocytes. These results explain prior modeling failures with the necessity for somatic LOH in a developmentally regulated cell type.