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Published 1 October 2001. doi:10.1083/jcb.200105052
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© The Rockefeller University Press, 0021-9525/2001/10/157 $5.00
The Journal of Cell Biology, Volume 155, Number 1, October 1, 2001 157-166

Article

Overexpression of Cbfa1 in osteoblasts inhibits osteoblast maturation and causes osteopenia with multiple fractures



Wenguang Liu1, Satoru Toyosawa2, Tatsuya Furuichi1, Naoko Kanatani1, Carolina Yoshida1,3, Yang Liu1, Miki Himeno1, Satoru Narai4, Akira Yamaguchi4 and Toshihisa Komori1,5

1 Department of Molecular Medicine, Osaka University Medical School, Suita, Osaka 565-0871, Japan
2 Department of Oral Pathology, Osaka University Faculty of Dentistry, Suita, Osaka 565-0871, Japan
3 Department of Orthodontics and Dentofacial Orthopedics, Osaka University Faculty of Dentistry, Suita, Osaka 565-0871, Japan
4 Department of Oral Pathology, Nagasaki University School of Dentistry, Nagasaki 852-8588, Japan
5 Japan Science and Technology Corporation, Kawaguchi City, Saitama Pref. 332-0012, Japan

Address correspondence to Toshihisa Komori, Dept. 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

Targeted disruption of core binding factor {alpha}1 (Cbfa1) showed that Cbfa1 is an essential transcription factor in osteoblast differentiation and bone formation. Furthermore, both in vitro and in vivo studies showed that Cbfa1 plays important roles in matrix production and mineralization. However, it remains to be clarified how Cbfa1 controls osteoblast differentiation, bone formation, and bone remodelling. To understand fully the physiological functions of Cbfa1, we generated transgenic mice that overexpressed Cbfa1 in osteoblasts using type I collagen promoter. Unexpectedly, Cbfa1 transgenic mice showed osteopenia with multiple fractures. Cortical bone, which was thin, porous, and enriched with osteopontin, was invaded by osteoclasts, despite the absence of acceleration of osteoclastogenesis. Although the number of neonatal osteoblasts was increased, their function was impaired in matrix production and mineralization. Furthermore, terminally differentiated osteoblasts, which strongly express osteocalcin, and osteocytes were diminished greatly, whereas less mature osteoblasts expressing osteopontin accumulated in adult bone. These data indicate that immature organization of cortical bone, which was caused by the maturational blockage of osteoblasts, led to osteopenia and fragility in transgenic mice, demonstrating that Cbfa1 inhibits osteoblast differentiation at a late stage.

Key Words: Cbfa1; osteoblast; osteocyte; transgenic mice; osteopenia


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