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Genes & Dev. 17 (16): 1979-1991

Copyright © 2003 by Cold Spring Harbor Laboratory Press.


Stat1 functions as a cytoplasmic attenuator of Runx2 in the transcriptional program of osteoblast differentiation

Sunhwa Kim1,5, Takako Koga1,2,5, Miho Isobe1,2, Britt E. Kern3, Taeko Yokochi1, Y. Eugene Chin4, Gerard Karsenty3, Tadatsugu Taniguchi1,6, and Hiroshi Takayanagi1,2

1 Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Tokyo 113-0033, Japan
2 PRESTO, Japan Science and Technology Corporation (JST), Kawaguchi, Saitama 332-0012, Japan
3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA
4 Department of Pathology and Laboratory Medicine, Brown University School of Medicine, Providence, Rhode Island 02912, USA

Abstract: Bone remodeling is central to maintaining the integrity of the skeletal system, wherein the developed bone is constantly renewed by the balanced action of osteoblastic bone formation and osteoclastic bone resorption. In the present study, we demonstrate a novel function of the Stat1 transcription factor in the regulation of bone remodeling. In the bone of the Stat1-deficient mice, excessive osteoclastogenesis is observed, presumably caused by a loss of negative regulation of osteoclast differentiation by interferon (IFN)-{beta}. However, the bone mass is unexpectedly increased in these mice. This increase is caused by excessive osteoblast differentiation, wherein Stat1 function is independent of IFN signaling. Actually, Stat1 interacts with Runx2 in its latent form in the cytoplasm, thereby inhibiting the nuclear localization of Runx2, an essential transcription factor for osteoblast differentiation. The new function of Stat1 does not require the Tyr 701 that is phosphorylated when Stat1 becomes a transcriptional activator. Our study provides a unique example in which a latent transcription factor attenuates the activity of another transcription factor in the cytoplasm, and reveals a new regulatory mechanism in bone remodeling.

Key Words: Stat1 • Runx2 • osteoblast • bone remodeling

Received for publication June 3, 2003. Accepted for publication June 24, 2003.

Supplemental material is available at

Article and publication are at

5 These authors contributed equally to this work.

6 Corresponding author. E-MAIL tada{at}; FAX 81-3-5841-3450.

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