The Journal of Experimental Medicine
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Published 21 March 2005. doi:10.1084/jem.20041097
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 6, 961-970
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ARTICLE

 The nucleocytoplasmic shuttling protein CIZ reduces adult bone mass by inhibiting bone morphogenetic protein–induced bone formation

Mikihiko Morinobu1, Tetsuya Nakamoto4, Kazunori Hino1, Kunikazu Tsuji1, Zhong-Jian Shen1, Kazuhisa Nakashima1, Akira Nifuji1, Haruyasu Yamamoto5, Hisamaru Hirai4, and Masaki Noda1,2,3

1 Department of Molecular Pharmacology, Tokyo Medical and Dental University
2 Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Core to Core Program for Advanced Bone and Joint Science, Japan Society for Promotion of Science, Tokyo 101-0062, Japan
3 Integrated Action Initiative, Core to Core Program for Advanced Bone and Joint Science, Japan Society for Promotion of Science, Tokyo 101-0062, Japan
4 University of Tokyo, Tokyo 113-8655, Japan
5 Ehime University, Ehime 791-0295, Japan

CORRESPONDENCE Masaki Noda: noda.mph{at}mri.tmd.ac.jp

Osteoporosis is a major health problem; however, the mechanisms regulating adult bone mass are poorly understood. Cas-interacting zinc finger protein (CIZ) is a nucleocytoplasmic shuttling protein that localizes at cell adhesion plaques that form where osteoblasts attach to substrate. To investigate the potential role of CIZ in regulating adult bone mass, we examined the bones in CIZ-deficient mice. Bone volume was increased and the rates of bone formation were increased in CIZ-deficient mice, whereas bone resorption was not altered. CIZ deficiency enhanced the levels of mRNA expression of genes encoding proteins related to osteoblastic phenotypes, such as alkaline phosphatase (ALP) as well as osterix mRNA expression in whole long bones. Bone marrow cells obtained from the femora of CIZ-deficient mice revealed higher ALP activity in culture and formed more mineralized nodules than wild-type cells. CIZ deficiency enhanced bone morphogenetic protein (BMP)–induced osteoblastic differentiation in bone marrow cells in cultures, indicating that BMP is the target of CIZ action. CIZ deficiency increased newly formed bone mass after femoral bone marrow ablation in vivo. Finally, BMP-2–induced bone formation on adult mouse calvariae in vivo was enhanced by CIZ deficiency. These results establish that CIZ suppresses the levels of adult bone mass through inhibition of BMP-induced activation of osteoblasts.

Abbreviations used: ALP, alkaline phosphatase; BMP, bone morphogenetic protein; CIZ, Cas-interacting zinc finger protein; COL, type I collagen; LRP5, low-density lipoprotein receptor-related protein 5; OPN, osteopontin; rh, recombinant human; TRAP, tartrate-resistant acid phosphatase.


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