Role of Mel1/Prdm16 in bone differentiation and morphology
Role of Mel1/Prdm16 in bone differentiation and morphology
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DOI：
10.1016/j.yexcr.2021.112969
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发表时间：
2022-01-15
影响因子：
3.7
通讯作者：
Morishita, Kazuhiro
中科院分区：
文献类型：
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作者：
Kaneda-Nakashima, Kazuko;Igawa, Kaori;Morishita, Kazuhiro
MEL 1（MDS 1/EVI 1-likegene 1/PRDM 16）是一种锌指蛋白，位于t（1; 3）（p36; q21）易位的人急性髓系白血病（AML）细胞染色体断裂点1 p36附近。Mel 1/Prdm 16不仅是白血病的致病基因，而且具有多种调节功能，如调节脂肪代谢。为了研究Mel 1/Prdm 16的功能，我们产生了Mel 1/Prdm 16缺陷小鼠，但是纯合缺陷（Mel 1/Prdm 16（-/-））在E11.5是胚胎致死的。杂合子小鼠在出生后的头骨和长骨中表现出异常的软骨和骨形成，这表明Mel 1/Prdm 16表达在骨发育中起着重要作用。在成骨细胞和软骨细胞系中，Mel 1/Prdm 16促进软骨细胞的分化并调节成骨细胞的分化。在分化的早期阶段，软骨细胞分化需要主调节因子Runx 2的瞬时抑制。然而，在Mel 1/Prdm 16抑制的ATDC 5细胞中，Runx 2的初始抑制是缺乏的，并且其表达在分化开始时上调，这表明在Mel 1/Prdm 16（+/-）间充质祖细胞中软骨形成分化受到抑制，因为Runx 2表达在分化的早期阶段上调。因此，Mel 1/Prdm 16基因可能参与骨软骨分化过程中Runx 2表达的早期抑制，并促进软骨分化。
MEL1 (MDS1/EVI1-like gene 1/PRDM16), a zinc finger protein, is located near the chromosomal breakpoint at 1p36 in human acute myeloid leukemia (AML) cells with the t (1; 3) (p36; q21) translocation. Mel1/Prdm16 is not only a causative gene of leukemia, but also has multiple regulatory functions, such as the regulation of fat metabolism. To investigate the function of Mel1/Prdm16, we generated Mel1/Prdm16-deficient mice, but homozygous deficiency (Mel1/Prdm16(-/-)) was embryonic lethal at E 11.5. Heterozygous mice showed abnormal cartilage and bone formation in the postnatal skull and long bones, suggesting that Mel1/Prdm16 expression plays an important role in bone development. In osteoblast and chondrocyte cell lines, Mel1/Prdm16 promotes the differentiation of chondrocytes and regulates the differentiation of osteoblasts. Transient repression of the master regulator Runx2 is required for chondrocyte differentiation at an early stage of differentiation. However, in Mel1/Prdm16-suppressed ATDC5 cells, the initial suppression of Runx2 was lacking and its expression was upregulated at the beginning of differentiation, suggesting that chondrogenic differentiation is suppressed in Mel1/Prdm16(+/-) mesenchymal progenitor cells because Runx2 expression is upregulated during the early stage of differentiation. Thus, the Mel1/Prdm16 gene may be involved in the early repression of Runx2 expression during osteochondral differentiation and promote chondrogenic differentiation.