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.
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 theskeletal
system, wherein the developed bone is constantly renewedby the balanced
action of osteoblastic bone formation and osteoclasticbone resorption. In the
present study, we demonstrate a novelfunction of the Stat1 transcription
factor in the regulationof bone remodeling. In the bone of the
Stat1-deficient mice,excessive osteoclastogenesis is observed,
presumably causedby a loss of negative regulation of osteoclast
differentiationby interferon (IFN)-. However, the bone mass is
unexpectedlyincreased in these mice. This increase is caused by excessive
osteoblast differentiation, wherein Stat1 function is independentof IFN
signaling. Actually, Stat1 interacts with Runx2 in itslatent form in the
cytoplasm, thereby inhibiting the nuclearlocalization of Runx2, an essential
transcription factor forosteoblast differentiation. The new function of Stat1
doesnot require the Tyr 701 that is phosphorylated when Stat1 becomesa
transcriptional activator. Our study provides a unique examplein which a
latent transcription factor attenuates the activityof another transcription
factor in the cytoplasm, and revealsa 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.
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 »
Influence of Signal Transducer and Activator of Transcription-1 Signaling on Thyroid Morphology and Function.
H. J. Kimura, R. Rocchi, M. A. Landek-Salgado, K. Suzuki, C. Y. Chen, M. Kimura, N. R. Rose, and P. Caturegli (2009)
Endocrinology
150, 3409-3416
|Abstract »|Full Text »|PDF »
Physical and Functional Interactions between STAT5 and Runx Transcription Factors.
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.
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.
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 »
Minireview: Transcriptional Regulation in Development of Bone.
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.
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 »
. 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. 
