Cbfb Regulates Bone Development by Stabilizing Runx Family Proteins

被引:67
|
作者
Qin, Xin [1 ]
Jiang, Qing [1 ]
Matsuo, Yuki [1 ]
Kawane, Tetsuya [1 ]
Komori, Hisato [1 ]
Moriishi, Takeshi [1 ]
Taniuchi, Ichiro [2 ]
Ito, Kosei [3 ]
Kawai, Yosuke [1 ,4 ]
Rokutanda, Satoshi [1 ,5 ]
Izumi, Shinichi [1 ]
Komori, Toshihisa [1 ]
机构
[1] Nagasaki Univ, Grad Sch Biomed Sci, Dept Cell Biol, Unit Basic Med Sci, Nagasaki 8528588, Japan
[2] RIKEN Res Ctr Allergy & Immunol, Lab Transcript Regulat, Yokohama, Kanagawa, Japan
[3] Nagasaki Univ, Grad Sch Biomed Sci, Dept Mol Bone Biol, Unit Basic Med Sci, Nagasaki 8528588, Japan
[4] Nagasaki Univ, Grad Sch Biomed Sci, Dept Regenerat Oral Surg, Unit Translat Med, Nagasaki 8528588, Japan
[5] Nagasaki Univ, Grad Sch Biomed Sci, Dept Oral & Maxillofacial Surg, Unit Translat Med, Nagasaki 8528588, Japan
关键词
CBFB; RUNX2; ENDOCHONDRAL OSSIFICATION; INTRAMEMBRANOUS OSSIFICATION; CCD; CLEIDOCRANIAL DYSPLASIA; TRANSCRIPTION FACTOR; PARATHYROID-HORMONE; SKELETAL DEVELOPMENT; BETA INTERACTS; IN-VIVO; GENE; BINDING; EXPRESSION; ENHANCER;
D O I
10.1002/jbmr.2379
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Runx family proteins, Runx1, Runx2, and Runx3, play important roles in skeletal development. Runx2 is required for osteoblast differentiation and chondrocyte maturation, and haplodeficiency of RUNX2 causes cleidocranial dysplasia, which is characterized by open fontanelles and sutures and hypoplastic clavicles. Cbfb forms a heterodimer with Runx family proteins and enhances their DNA-binding capacity. Cbfb-deficient (Cbfb(-/-)) mice die at midgestation because of the lack of fetal liver hematopoiesis. We previously reported that the partial rescue of hematopoiesis in Cbfb(-/-) mice revealed the requirement of Cbfb in skeletal development. However, the precise functions of Cbfb in skeletal development still remain to be clarified. We deleted Cbfb in mesenchymal cells giving rise to both chondrocyte and osteoblast lineages by mating Cbfb(fl/fl) mice with Dermo1 Cre knock-in mice. Cbfb(fl/fl/Cre) mice showed dwarfism, both intramembranous and endochondral ossifications were retarded, and chondrocyte maturation and proliferation and osteoblast differentiation were inhibited. The differentiation of chondrocytes and osteoblasts were severely inhibited in vitro, and the reporter activities of Ihh, Col10a1, and Bglap2 promoter constructs were reduced in Cbfb(fl/fl/Cre) chondrocytes or osteoblasts. The proteins of Runx1, Runx2, and Runx3 were reduced in the cartilaginous limb skeletons and calvariae of Cbfb(fl/fl/Cre) embryos compared with the respective protein in the respective tissue of Cbfb(fl/fl) embryos at E15.5, although the reduction of Runx2 protein in calvariae was much milder than that in cartilaginous limb skeletons. All of the Runx family proteins were severely reduced in Cbfb(fl/fl/Cre) primary osteoblasts, and Runx2 protein was less stable in Cbfb(fl/fl/Cre) osteoblasts than Cbfb(fl/fl) osteoblasts. These findings indicate that Cbfb is required for skeletal development by regulating chondrocyte differentiation and proliferation and osteoblast differentiation; that Cbfb plays an important role in the stabilization of Runx family proteins; and that Runx2 protein stability is less dependent on Cbfb in calvariae than in cartilaginous limb skeletons. (c) 2014 American Society for Bone and Mineral Research.
引用
收藏
页码:706 / 714
页数:9
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