Mutant IDH is sufficient to initiate enchondromatosis in mice
Mutant IDH is sufficient to initiate enchondromatosis in mice
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DOI：
10.1073/pnas.1424400112
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发表时间：
2015-03-03
影响因子：
11.1
通讯作者：
Alman, Benjamin A.
中科院分区：
文献类型：
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作者：
Hirata, Makoto;Sasaki, Masato;Alman, Benjamin A.
内生性软骨瘤是良性软骨肿瘤，也是恶性软骨肉瘤的前驱症状。异柠檬酸脱氢酶基因(IDH1和IDH2)的体细胞突变存在于大多数这些类型的肿瘤中。这些突变是如何导致内脏软骨瘤的尚不清楚。在这里，我们确定了人类内生性软骨瘤和软骨肉瘤中IDH突变的谱系，并研究了它们在小鼠中的影响。发现了广泛的突变，包括以前未报道的IDH1-R132Q突变。这些突变具有催化α-酮戊二酸生成D-2-羟基戊二酸(D-2HG)的活性。在表达2型胶原的细胞中，表达IDH1-R132Q一个等位基因的小鼠表现出生长板紊乱，并持续表达X型软骨细胞。软骨细胞培养结果显示，经IDH1-R132Q或2HG处理后，肥大软骨细胞的增殖和特征性基因表达增加。Col2a1-Cre；IDH1-R132Q突变敲入小鼠(突变等位基因在软骨细胞中表达)在新生儿期后不能存活。Col2a1-Cre/ERT2；IDH1-R132突变型条件性敲入小鼠在断奶后用他莫昔芬诱发Cre，可形成多个内生瘤样病变。综上所述，这些数据表明，突变的IDH或D-2HG导致软骨细胞持续存在，导致生长板细胞以内生性软骨瘤的形式存在于骨骼中。
Enchondromas are benign cartilage tumors and precursors to malignant chondrosarcomas. Somatic mutations in the isocitrate dehydrogenase genes (IDH1 and IDH2) are present in the majority of these tumor types. How these mutations cause enchondromas is unclear. Here, we identified the spectrum of IDH mutations in human enchondromas and chondrosarcomas and studied their effects in mice. A broad range of mutations was identified, including the previously unreported IDH1-R132Q mutation. These mutations harbored enzymatic activity to catalyze alpha-ketoglutarate to D-2-hydroxyglutarate (D-2HG). Mice expressing Idh1-R132Q in one allele in cells expressing type 2 collagen showed a disordered growth plate, with persistence of type X-expressing chondrocytes. Chondrocyte cell cultures from these animals or controls showed that there was an increase in proliferation and expression of genes characteristic of hypertrophic chondrocytes with expression of Idh1-R132Q or 2HG treatment. Col2a1-Cre;Idh1-R132Q mutant knock-in mice (mutant allele expressed in chondrocytes) did not survive after the neonatal stage. Col2a1-Cre/ERT2;Idh1-R132 mutant conditional knock-in mice, in which Cre was induced by tamoxifen after weaning, developed multiple enchondroma-like lesions. Taken together, these data show that mutant IDH or D-2HG causes persistence of chondrocytes, giving rise to rests of growth-plate cells that persist in the bone as enchondromas.