CCAAT/enhancer-binding protein homologous protein (CHOP) regulates osteoblast differentiation
CCAAT/enhancer-binding protein homologous protein (CHOP) regulates osteoblast differentiation
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DOI：
10.1128/mcb.02429-05
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发表时间：
2006-08-01
影响因子：
5.3
通讯作者：
Imamura, Takeshi
中科院分区：
文献类型：
--
作者：
Shirakawa, Ken;Maeda, Shingo;Imamura, Takeshi
成骨细胞的分化受包括信号转导和基因表达在内的复杂活动的控制，Runx2和Osterix在这一过程中起主要调节作用。最近，CCAAT/增强子结合蛋白（C/ ebp）被报道除了调节脂肪生成外还调节骨生成。然而，C/EBP转录因子在控制成骨细胞分化中的作用尚未完全阐明。在这里，我们发现C/EBP同源蛋白（CHOP，也称为C/EBP zeta）在骨以及间充质祖细胞和原代成骨细胞中表达。CHOP的过表达降低了初代成骨细胞碱性磷酸酶的活性，抑制了钙化骨结节的形成。缺乏CHOP的成骨细胞比野生型成骨细胞分化更强，提示内源性CHOP在抑制成骨细胞分化中起重要作用。此外，内源性CHOP诱导骨形态发生蛋白（BMP）处理后的颅骨成骨细胞分化。CHOP与C/EBP β形成异源二聚体，抑制C/EBP β的dna结合活性和runx2结合活性，导致骨钙素基因转录受到抑制。这些发现表明CHOP作为C/EBP β的显性阴性抑制剂，阻止成骨细胞分化，但以细胞类型依赖的方式促进BMP信号传导。因此，内源性CHOP在调节成骨细胞分化和骨形成中可能具有双重作用。
Differentiation of committed osteoblasts is controlled by complex activities involving signal transduction and gene expression, and Runx2 and Osterix function as master regulators for this process. Recently, CCAAT/enhancer-binding proteins (C/EBPs) have been reported to regulate osteogenesis in addition to adipogenesis. However, the roles of C/EBP transcription factors in the control of osteoblast differentiation have yet to be fully elucidated. Here we show that C/EBP homologous protein (CHOP; also known as C/EBP zeta) is expressed in bone as well as in mesenchymal progenitors and primary osteoblasts. Overexpression of CHOP reduces alkaline phosphatase activity in primary osteoblasts and suppresses the formation of calcified bone nodules. CHOP-deficient osteoblasts differentiate more strongly than their wild-type counterparts, suggesting that endogenous CHOP plays an important role in the inhibition of osteoblast differentiation. Furthermore, endogenous CHOP induces differentiation of calvarial osteoblasts upon bone morphogenetic protein (BMP) treatment. CHOP forms heterodimers with C/EBP beta and inhibits the DNA-binding activity as well as Runx2-binding activity of C/EBP beta, leading to inhibition of osteocalcin gene transcription. These findings indicate that CHOP acts as a dominant-negative inhibitor of C/EBP beta and prevents osteoblast differentiation but promotes BMP signaling in a cell-type-dependent manner. Thus, endogenous CHOP may have dual roles in regulating osteoblast differentiation and bone formation.