Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

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

Copyright © 2003 by Cold Spring Harbor Laboratory Press.


RESEARCH PAPER

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 http://www.genesdev.org.

Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1119303.

5 These authors contributed equally to this work.

6 Corresponding author. E-MAIL tada{at}m.u-tokyo.ac.jp; FAX 81-3-5841-3450.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Development of the Endochondral Skeleton.
F. Long and D. M. Ornitz (2013)
Cold Spring Harb Perspect Biol 5, a008334
   Abstract »    Full Text »    PDF »
miR-34s inhibit osteoblast proliferation and differentiation in the mouse by targeting SATB2.
J. Wei, Y. Shi, L. Zheng, B. Zhou, H. Inose, J. Wang, X. E. Guo, R. Grosschedl, and G. Karsenty (2012)
J. Cell Biol. 197, 509-521
   Abstract »    Full Text »    PDF »
Foxo1 Mediates Insulin-like Growth Factor 1 (IGF1)/Insulin Regulation of Osteocalcin Expression by Antagonizing Runx2 in Osteoblasts.
S. Yang, H. Xu, S. Yu, H. Cao, J. Fan, C. Ge, R. T. Fransceschi, H. H. Dong, and G. Xiao (2011)
J. Biol. Chem. 286, 19149-19158
   Abstract »    Full Text »    PDF »
IL-27 Abrogates Receptor Activator of NF-{kappa}B Ligand-Mediated Osteoclastogenesis of Human Granulocyte-Macrophage Colony-Forming Unit Cells through STAT1-Dependent Inhibition of c-Fos.
M. Furukawa, H. Takaishi, J. Takito, M. Yoda, S. Sakai, T. Hikata, A. Hakozaki, S. Uchikawa, M. Matsumoto, K. Chiba, et al. (2009)
J. Immunol. 183, 2397-2406
   Abstract »    Full Text »    PDF »
Physical and Functional Interactions between STAT5 and Runx Transcription Factors.
S. Ogawa, M. Satake, and K. Ikuta (2008)
J. Biochem. 143, 695-709
   Abstract »    Full Text »    PDF »
Differential Effects of CpG DNA on IFN-beta Induction and STAT1 Activation in Murine Macrophages versus Dendritic Cells: Alternatively Activated STAT1 Negatively Regulates TLR Signaling in Macrophages.
K. Schroder, M. Spille, A. Pilz, J. Lattin, K. A. Bode, K. M. Irvine, A. D. Burrows, T. Ravasi, H. Weighardt, K. J. Stacey, et al. (2007)
J. Immunol. 179, 3495-3503
   Abstract »    Full Text »    PDF »
PIASxbeta is a key regulator of osterix transcriptional activity and matrix mineralization in osteoblasts.
Md. M. Ali, T. Yoshizawa, O. Ishibashi, A. Matsuda, M. Ikegame, J. Shimomura, H. Mera, K. Nakashima, and H. Kawashima (2007)
J. Cell Sci. 120, 2565-2573
   Abstract »    Full Text »    PDF »
JAK-STAT Signaling: From Interferons to Cytokines.
C. Schindler, D. E. Levy, and T. Decker (2007)
J. Biol. Chem. 282, 20059-20063
   Full Text »    PDF »
Inhibition of Prostate Tumor Growth and Bone Remodeling by the Vascular Targeting Agent VEGF121/rGel..
K. A. Mohamedali, A. T. Poblenz, C. R. Sikes, N. M. Navone, P. E. Thorpe, B. G. Darnay, and M. G. Rosenblum (2006)
Cancer Res. 66, 10919-10928
   Abstract »    Full Text »    PDF »
Regulation of adult bone mass by the zinc finger adapter protein schnurri-3..
D. C. Jones, M. N. Wein, M. Oukka, J. G. Hofstaetter, M. J. Glimcher, and L. H. Glimcher (2006)
Science 312, 1223-1227
   Abstract »    Full Text »    PDF »
Role of STAT3 in Type I Interferon Responses: NEGATIVE REGULATION OF STAT1-DEPENDENT INFLAMMATORY GENE ACTIVATION.
H. H. Ho and L. B. Ivashkiv (2006)
J. Biol. Chem. 281, 14111-14118
   Abstract »    Full Text »    PDF »
Cooperative Interactions between Activating Transcription Factor 4 and Runx2/Cbfa1 Stimulate Osteoblast-specific Osteocalcin Gene Expression.
G. Xiao, D. Jiang, C. Ge, Z. Zhao, Y. Lai, H. Boules, M. Phimphilai, X. Yang, G. Karsenty, and R. T. Franceschi (2005)
J. Biol. Chem. 280, 30689-30696
   Abstract »    Full Text »    PDF »
RUNX3, A Novel Tumor Suppressor, Is Frequently Inactivated in Gastric Cancer by Protein Mislocalization.
K. Ito, Q. Liu, M. Salto-Tellez, T. Yano, K. Tada, H. Ida, C. Huang, N. Shah, M. Inoue, A. Rajnakova, et al. (2005)
Cancer Res. 65, 7743-7750
   Abstract »    Full Text »    PDF »
Interferon-{gamma}-activated STAT-1{alpha} suppresses MMP-9 gene transcription by sequestration of the coactivators CBP/p300.
Z. Ma, M. J. Chang, R. C. Shah, and E. N. Benveniste (2005)
J. Leukoc. Biol. 78, 515-523
   Abstract »    Full Text »    PDF »
Homeostatic Role of Interferons Conferred by Inhibition of IL-1-Mediated Inflammation and Tissue Destruction.
X. Hu, H. H. Ho, O. Lou, C. Hidaka, and L. B. Ivashkiv (2005)
J. Immunol. 175, 131-138
   Abstract »    Full Text »    PDF »
Oct-1 Counteracts Autoinhibition of Runx2 DNA Binding To Form a Novel Runx2/Oct-1 Complex on the Promoter of the Mammary Gland-Specific Gene {beta}-casein.
C. K. Inman, N. Li, and P. Shore (2005)
Mol. Cell. Biol. 25, 3182-3193
   Abstract »    Full Text »    PDF »
The high mobility group transcription factor Sox8 is a negative regulator of osteoblast differentiation.
K. Schmidt, T. Schinke, M. Haberland, M. Priemel, A. F. Schilling, C. Mueldner, J. M. Rueger, E. Sock, M. Wegner, and M. Amling (2005)
J. Cell Biol. 168, 899-910
   Abstract »    Full Text »    PDF »
Coordinated Activation of Notch, Wnt, and Transforming Growth Factor-{beta} Signaling Pathways in Bone Morphogenic Protein 2-induced Osteogenesis: Notch TARGET GENE Hey1 INHIBITS MINERALIZATION AND Runx2 TRANSCRIPTIONAL ACTIVITY.
N. Zamurovic, D. Cappellen, D. Rohner, and M. Susa (2004)
J. Biol. Chem. 279, 37704-37715
   Abstract »    Full Text »    PDF »
ChIP Display: novel method for identification of genomic targets of transcription factors.
A. Barski and B. Frenkel (2004)
Nucleic Acids Res. 32, e104
   Abstract »    Full Text »    PDF »
Stat1 Controls Postnatal Bone Formation by Regulating Fibroblast Growth Factor Signaling in Osteoblasts.
L. Xiao, T. Naganawa, E. Obugunde, G. Gronowicz, D. M. Ornitz, J. D. Coffin, and M. M. Hurley (2004)
J. Biol. Chem. 279, 27743-27752
   Abstract »    Full Text »    PDF »
Sequestration of Thermogenic Transcription Factors in the Cytoplasm during Development of Brown Adipose Tissue.
J. S. Rim, B. Xue, B. Gawronska-Kozak, and L. P. Kozak (2004)
J. Biol. Chem. 279, 25916-25926
   Abstract »    Full Text »    PDF »
Homeobox Protein Msx2 Acts as a Molecular Defense Mechanism for Preventing Ossification in Ligament Fibroblasts.
T. Yoshizawa, F. Takizawa, F. Iizawa, O. Ishibashi, H. Kawashima, A. Matsuda, N. Endo, and H. Kawashima (2004)
Mol. Cell. Biol. 24, 3460-3472
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882