Skeletal malformations caused by overexpression of Cbfa1 or its dominant negative form in chondrocytes

被引:316
作者
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
机构
[1] Osaka Univ, Sch Med, Dept Mol Med, Suita, Osaka 5650871, Japan
[2] Osaka Univ, Fac Dent, Dept Oral Anat & Dev Biol, Suita, Osaka 5650871, Japan
[3] Osaka Univ, Fac Dent, Dept Orthodont & Dentofacial Orthoped, Suita, Osaka 5650871, Japan
[4] Osaka Univ, Fac Dent, Dept Biochem, Suita, Osaka 5650871, Japan
[5] Kansai Rosai Hosp, Amagasaki, Hyogo 6608511, Japan
[6] Japan Sci & Technol Corp, Precursory Res Embryon Sci & Technol, Form & Funct, Suita, Osaka 5650871, Japan
关键词
chondrocyte; Cbfa1; transgenic mice; endochondral ossification; permanent cartilage;
D O I
10.1083/jcb.153.1.87
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:87 / 99
页数:13
相关论文
共 38 条
[1]   MODULATED EXPRESSION OF TYPE-X COLLAGEN IN THE MECKELS CARTILAGE WITH DIFFERENT DEVELOPMENTAL FATES [J].
CHUNG, KS ;
PARK, HH ;
TING, K ;
TAKITA, H ;
APTE, SS ;
KUBOKI, Y ;
NISHIMURA, I .
DEVELOPMENTAL BIOLOGY, 1995, 170 (02) :387-396
[2]   Osf2/Cbfa1: A transcriptional activator of osteoblast differentiation [J].
Ducy, P ;
Zhang, R ;
Geoffroy, V ;
Ridall, AL ;
Karsenty, G .
CELL, 1997, 89 (05) :747-754
[3]   A Cbfa1-dependent genetic pathway controls bone formation beyond embryonic development [J].
Ducy, P ;
Starbuck, M ;
Priemel, M ;
Shen, JH ;
Pinero, G ;
Geoffroy, V ;
Amling, M ;
Karsenty, G .
GENES & DEVELOPMENT, 1999, 13 (08) :1025-1036
[4]   Cbfa1 is a positive regulatory factor in chondrocyte maturation [J].
Enomoto, H ;
Enomoto-Iwamoto, M ;
Iwamoto, M ;
Nomura, S ;
Himeno, M ;
Kitamura, Y ;
Kishimoto, T ;
Komori, T .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (12) :8695-8702
[5]   Bone morphogenetic protein signaling is required for maintenance of differentiated phenotype, control of proliferation, and hypertrophy in chondrocytes [J].
Enomoto-Iwamoto, M ;
Iwamoto, M ;
Mukudai, Y ;
Kawakami, Y ;
Nohno, T ;
Higuchi, Y ;
Takemoto, S ;
Ohuchi, H ;
Noji, S ;
Kurisu, K .
JOURNAL OF CELL BIOLOGY, 1998, 140 (02) :409-418
[6]  
Gilbert SF., 1997, DEV BIOL, P351
[7]   Cbfa1 isoforms exert functional differences in osteoblast differentiation [J].
Harada, H ;
Tagashira, S ;
Fujiwara, M ;
Ogawa, S ;
Katsumata, T ;
Yamaguchi, A ;
Komori, T ;
Nakatsuka, M .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (11) :6972-6978
[8]  
Inada M, 1999, DEV DYNAM, V214, P279, DOI 10.1002/(SICI)1097-0177(199904)214:4<279::AID-AJA1>3.0.CO
[9]  
2-W
[10]   HYPERTROPHY AND CALCIFICATION OF RABBIT PERMANENT CHONDROCYTES IN PELLETED CULTURES - SYNTHESIS OF ALKALINE-PHOSPHATASE AND 1,25-DIHYDROXYCHOLECALCIFEROL RECEPTOR [J].
IWAMOTO, M ;
SATO, K ;
NAKASHIMA, K ;
SHIMAZU, A ;
KATO, Y .
DEVELOPMENTAL BIOLOGY, 1989, 136 (02) :500-507