Skeletal Malformations Caused by Overexpression of Cbfa1 or Its Dominant Negative Form in Chondrocytes

doi:10.1083/jcb.153.1.87

Published online 2 April 2001. doi:10.1083/jcb.153.1.87

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© The Rockefeller University Press, 0021-9525/2001/4/87/ $5.00
The Journal of Cell Biology, Volume 153, Number 1, April 2, 2001 87-100

Original Article

Skeletal Malformations Caused by Overexpression of Cbfa1 or Its Dominant Negative Form in Chondrocytes

Chisato Ueta^a, Masahiro Iwamoto^b, Naoko Kanatani^a, Carolina Yoshida^a,c, Yang Liu^a, Motomi Enomoto-Iwamoto^d, Tomoharu Ohmori^b, Hirayuki Enomoto^a, Ken Nakata^e, Kenji Takada^c, Kojiro Kurisu^b, and Toshihisa Komori^a,f
^a Department of Molecular Medicine, Osaka University Medical School, Suita, Osaka 565-0871, Japan
^b Department of Oral Anatomy and Developmental Biology, Osaka University Faculty of Dentistry, Suita, Osaka 565-0871, Japan
^c Department of Orthodontics and Dentofacial Orthopedics, Osaka University Faculty of Dentistry, Suita, Osaka 565-0871, Japan
^d Department of Biochemistry, Osaka University Faculty of Dentistry, Suita, Osaka 565-0871, Japan
^e Orthopedic Sports Medicine, Kansai Rosai Hospital, Amagasaki, Hyogo 660-8511, Japan
^f Form and Function, Precursory Research for Embryonic Science and Technology, Japan Science and Technology Corporation, Suita, Osaka 565-0871, Japan

Correspondence to: Toshihisa Komori, Department of Molecular Medicine, Osaka University Medical School, 2-2 Yamada-oka Suita, Osaka 565-0871, Japan. Tel:81-6-6879-7590 Fax:81-6-6879-7796 E-mail:komorit{at}imed3.med.osaka-u.ac.jp.

During skeletogenesis, cartilage develops to either permanentcartilage that persists through life or transient cartilagethat is eventually replaced by bone. However, the mechanismby which cartilage phenotype is specified remains unclarified.Core binding factor ${alpha}$ 1 (Cbfa1) is an essential transcriptionfactor for osteoblast differentiation and bone formation andhas the ability to stimulate chondrocyte maturation in vitro.To understand the roles of Cbfa1 in chondrocytes during skeletaldevelopment, we generated transgenic mice that overexpress Cbfa1or a dominant negative (DN)-Cbfa1 in chondrocytes under thecontrol of a type II collagen promoter/enhancer. Both typesof transgenic mice displayed dwarfism and skeletal malformations,which, however, resulted from opposite cellular phenotypes.Cbfa1 overexpression caused acceleration of endochondral ossificationdue to precocious chondrocyte maturation, whereas overexpressionof DN-Cbfa1 suppressed maturation and delayed endochondral ossification.In addition, Cbfa1 transgenic mice failed to form most of theirjoints and permanent cartilage entered the endochondral pathway,whereas most chondrocytes in DN-Cbfa1 transgenic mice retaineda marker for permanent cartilage. These data show that temporallyand spatially regulated expression of Cbfa1 in chondrocytesis required for skeletogenesis, including formation of joints,permanent cartilages, and endochondral bones.

Key Words: chondrocyte, Cbfa1, transgenic mice, endochondral ossification,permanent cartilage

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Canalis, E., Economides, A. N., Gazzerro, E. (2003). Bone Morphogenetic Proteins, Their Antagonists, and the Skeleton. Endocr. Rev. 24: 218-235 [Abstract] [Full Text]
Yang, Y., Topol, L., Lee, H., Wu, J. (2003). Wnt5a and Wnt5b exhibit distinct activities in coordinating chondrocyte proliferation and differentiation. Development 130: 1003-1015 [Abstract] [Full Text]
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Zeng, L., Kempf, H., Murtaugh, L. C., Sato, M. E., Lassar, A. B. (2002). Shh establishes an Nkx3.2/Sox9 autoregulatory loop that is maintained by BMP signals to induce somitic chondrogenesis. Genes Dev. 16: 1990-2005 [Abstract] [Full Text]
Mengshol, J. A., Vincenti, M. P., Brinckerhoff, C. E. (2001). IL-1 induces collagenase-3 (MMP-13) promoter activity in stably transfected chondrocytic cells: requirement for Runx-2 and activation by p38 MAPK and JNK pathways. Nucleic Acids Res 29: 4361-4372 [Abstract] [Full Text]
Liu, W., Toyosawa, S., Furuichi, T., Kanatani, N., Yoshida, C., Liu, Y., Himeno, M., Narai, S., Yamaguchi, A., Komori, T. (2001). Overexpression of Cbfa1 in osteoblasts inhibits osteoblast maturation and causes osteopenia with multiple fractures. JCB 155: 157-166 [Abstract] [Full Text]
Banerjee, C., Javed, A., Choi, J.-Y., Green, J., Rosen, V., van Wijnen, A. J., Stein, J. L., Lian, J. B., Stein, G. S. (2001). Differential Regulation of the Two Principal Runx2/Cbfa1 N-Terminal Isoforms in Response to Bone Morphogenetic Protein-2 during Development of the Osteoblast Phenotype. Endocrinology 142: 4026-4039 [Abstract] [Full Text]