Ueta C, Iwamoto M, Kanatani N, Yoshida C, Liu Y, Enomoto-Iwamoto M, Ohmori T, Enomoto H, Nakata K, Takada K, Kurisu K, Komori T
Department of Molecular Medicine, Osaka University Medical School, Suita, Osaka 565-0871, Japan.
J Cell Biol. 2001 Apr 2;153(1):87-100. doi: 10.1083/jcb.153.1.87.
During skeletogenesis, cartilage develops to either permanent cartilage that persists through life or transient cartilage that is eventually replaced by bone. However, the mechanism by which cartilage phenotype is specified remains unclarified. Core binding factor alpha1 (Cbfa1) is an essential transcription factor for osteoblast differentiation and bone formation and has the ability to stimulate chondrocyte maturation in vitro. To understand the roles of Cbfa1 in chondrocytes during skeletal development, we generated transgenic mice that overexpress Cbfa1 or a dominant negative (DN)-Cbfa1 in chondrocytes under the control of a type II collagen promoter/enhancer. Both types of transgenic mice displayed dwarfism and skeletal malformations, which, however, resulted from opposite cellular phenotypes. Cbfa1 overexpression caused acceleration of endochondral ossification due to precocious chondrocyte maturation, whereas overexpression of DN-Cbfa1 suppressed maturation and delayed endochondral ossification. In addition, Cbfa1 transgenic mice failed to form most of their joints and permanent cartilage entered the endochondral pathway, whereas most chondrocytes in DN-Cbfa1 transgenic mice retained a marker for permanent cartilage. These data show that temporally and spatially regulated expression of Cbfa1 in chondrocytes is required for skeletogenesis, including formation of joints, permanent cartilages, and endochondral bones.
在骨骼发生过程中，软骨发育为终生存在的永久性软骨或最终被骨替代的临时性软骨。然而，软骨表型确定的机制仍不清楚。核心结合因子α1（Cbfa1）是成骨细胞分化和骨形成所必需的转录因子，并且在体外具有刺激软骨细胞成熟的能力。为了了解Cbfa1在骨骼发育过程中软骨细胞中的作用，我们构建了在II型胶原启动子/增强子控制下在软骨细胞中过表达Cbfa1或显性负性（DN）-Cbfa1的转基因小鼠。两种类型的转基因小鼠均表现出侏儒症和骨骼畸形，然而，这是由相反的细胞表型导致的。Cbfa1过表达由于软骨细胞早熟而导致软骨内成骨加速，而DN-Cbfa1过表达则抑制成熟并延迟软骨内成骨。此外，Cbfa1转基因小鼠未能形成大部分关节，永久性软骨进入软骨内成骨途径，而DN-Cbfa1转基因小鼠中的大多数软骨细胞保留了永久性软骨的标志物。这些数据表明，软骨细胞中Cbfa1在时间和空间上的调控表达是骨骼发生所必需的，包括关节、永久性软骨和软骨内骨的形成。
