Antxr1, Which is a Target of Runx2, Regulates Chondrocyte Proliferation and Apoptosis
Antxr1, Which is a Target of Runx2, Regulates Chondrocyte Proliferation and Apoptosis
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DOI：
10.3390/ijms21072425
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发表时间：
2020-04-01
影响因子：
5.6
通讯作者：
Komori, Toshihisa
中科院分区：
文献类型：
--
作者：
Jiang, Qing;Qin, Xin;Komori, Toshihisa
Antxr1/Tem8在肿瘤内皮细胞中高度表达，是炭疽毒素的受体。Antxr1突变导致GAPO综合征，其特征在于生长迟缓、脱发、假性无牙和视神经萎缩。然而，生长迟缓的机制仍有待澄清。Runx2是成骨细胞分化和软骨细胞成熟所必需的，并通过Ihh诱导调节软骨细胞增殖。在软骨细胞中Runx2靶基因的搜索中，我们发现Antxr1的表达被Runx2上调。Antxr1在软骨组织中高度表达，并受Runx2直接调控。在骨骼发育中，软骨内骨化的过程在野生型和Antxr1（-/-）小鼠中进行相似。然而，Antxr1（-/-）小鼠的四肢从胚胎第16.5天开始比野生型小鼠短，这是由于软骨细胞增殖减少。软骨细胞特异性Antxr1转基因小鼠表现出四肢缩短，尽管软骨内骨化的过程与野生型小鼠一样进行。软骨细胞BrdU摄取和凋亡均增加，高凋亡区矿化。这些结果表明，Antxr1，其表达受Runx2调节，在软骨细胞增殖中起重要作用，并且Antxr1的过表达导致软骨细胞凋亡伴随基质矿化。
Antxr1/Tem8 is highly expressed in tumor endothelial cells and is a receptor for anthrax toxin. Mutation of Antxr1 causes GAPO syndrome, which is characterized by growth retardation, alopecia, pseudo-anodontia, and optic atrophy. However, the mechanism underlying the growth retardation remains to be clarified. Runx2 is essential for osteoblast differentiation and chondrocyte maturation and regulates chondrocyte proliferation through Ihh induction. In the search of Runx2 target genes in chondrocytes, we found that Antxr1 expression is upregulated by Runx2. Antxr1 was highly expressed in cartilaginous tissues and was directly regulated by Runx2. In skeletal development, the process of endochondral ossification proceeded similarly in wild-type and Antxr1(-/-) mice. However, the limbs of Antxr1(-/-) mice were shorter than those of wild-type mice from embryonic day 16.5 due to the reduced chondrocyte proliferation. Chondrocyte-specific Antxr1 transgenic mice exhibited shortened limbs, although the process of endochondral ossification proceeded as in wild-type mice. BrdU-uptake and apoptosis were both increased in chondrocytes, and the apoptosis-high regions were mineralized. These findings indicated that Antxr1, of which the expression is regulated by Runx2, plays an important role in chondrocyte proliferation and that overexpression of Antxr1 causes chondrocyte apoptosis accompanied by matrix mineralization.