The Nuclear Factor of Activated T Cells (Nfat) Transcription Factor Nfatp (Nfatc2) Is a Repressor of Chondrogenesis

doi:10.1084/jem.191.1.9

This Article

	Full Text
	Full Text (PDF, 570K)
	PPT slides of all figures
	Alert me when this article is cited
	Citation Map

Services

	Email this article
	Similar articles in this journal
	Similar articles in PubMed
	Alert me to new content in the JEM
	Download to citation manager

Citing Articles

	Citing Articles via HighWire
	Citing Articles via CrossRef
	Citing Articles via Google Scholar

Google Scholar

	Articles by Ranger, A. M.
	Articles by Glimcher, L. H.
	Search for Related Content

PubMed

	PubMed Citation
	Articles by Ranger, A. M.
	Articles by Glimcher, L. H.


Social Bookmarking

	What's this?

© The Rockefeller University Press, 0022-1007/2000/1/9/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 1, January 3, 2000 9-22

Original Article

The Nuclear Factor of Activated T Cells (Nfat) Transcription Factor Nfatp (Nfatc2) Is a Repressor of Chondrogenesis

Ann M. Ranger^a, Louis C. Gerstenfeld^d, Jinxi Wang^b, Tamiyo Kon^d^,e, Hyunsu Bae^a, Ellen M. Gravallese^c, Melvin J. Glimcher^b, and Laurie H. Glimcher^a^,c

^a Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115
^b Laboratory for the Study of Skeletal Disorders and Rehabilitation, Department of Orthopedic Surgery, Harvard Medical School, Children's Hospital, Boston, Massachusetts 02115
^c Department of Medicine, Harvard Medical School, and Division of Rheumatology, Brigham and Women's Hospital and Beth Israel Deaconess, Boston, Massachusetts 02115
^d Musculoskeletal Research Laboratory, Department of Orthopaedic Surgery, Boston University Medical Center, Boston, Massachusetts 02118
^e Department of Orthopaedic Surgery, School of Medicine, Chiba University, Chiba 260-8677, Japan
Department of Immunology and Infectious Diseases, Harvard School of Public Health, 651 Huntington Ave., Boston, MA 02115.617-432-0084617-432-0622

lglimche{at}hsph.harvard.edu

Nuclear factor of activated T cells (NFAT) transcription factorsregulate gene expression in lymphocytes and control cardiacvalve formation. Here, we report that NFATp regulates chondrogenesisin the adult animal. In mice lacking NFATp, resident cells inthe extraarticular connective tissues spontaneously differentiateto cartilage. These cartilage cells progressively differentiateand the tissue undergoes endochondral ossification, recapitulatingthe development of endochondral bone. Proliferation of alreadyexisting articular cartilage cells also occurs in some olderanimals. At both sites, neoplastic changes in the cartilagecells occur. Consistent with these data, NFATp expression isregulated in mesenchymal stem cells induced to differentiatealong a chondrogenic pathway. Lack of NFATp in articular cartilagecells results in increased expression of cartilage markers,whereas overexpression of NFATp in cartilage cell lines extinguishesthe cartilage phenotype. Thus, NFATp is a repressor of cartilagecell growth and differentiation and also has the propertiesof a tumor suppressor.

Key Words: cartilage • NFATp • mesenchymal stem cells • chondrosarcoma • differentiation

Abbreviations used in this paper: BMP, bone morphogenetic protein;CDMP, cartilage-derived morphogenetic protein; COMP, cartilageoligomeric protein; EA, extraarticular cartilage cell line;GDF, growth/differentiation factor; HPRT, hypoxanthine phosphoribosyltransferase;MSC, mesenchymal stem cell; NFAT, nuclear factor of activatedT cells; PTHrP, parathyroid hormone–related protein; RT,reverse transcription; wt, wild-type.

Add to CiteULike CiteULike Add to Complore Complore Add to Connotea Connotea Add to Del.icio.us Del.icio.us Add to Digg Digg Facebook Add to Reddit Reddit Add to Technorati Technorati Twitter What's this?

This article has been cited by other articles:

Robbs, B. K., Cruz, A. L. S., Werneck, M. B. F., Mognol, G. P., Viola, J. P. B. (2008). Dual Roles for NFAT Transcription Factor Genes as Oncogenes and Tumor Suppressors. Mol. Cell. Biol. 28: 7168-7181 [Abstract] [Full Text]
Bourajjaj, M., Armand, A.-S., da Costa Martins, P. A., Weijts, B., van der Nagel, R., Heeneman, S., Wehrens, X. H., De Windt, L. J. (2008). NFATc2 Is a Necessary Mediator of Calcineurin-dependent Cardiac Hypertrophy and Heart Failure. J. Biol. Chem. 283: 22295-22303 [Abstract] [Full Text]
Olabisi, O. A., Soto-Nieves, N., Nieves, E., Yang, T. T. C., Yang, X., Yu, R. Y. L., Suk, H. Y., Macian, F., Chow, C.-W. (2008). Regulation of Transcription Factor NFAT by ADP-Ribosylation. Mol. Cell. Biol. 28: 2860-2871 [Abstract] [Full Text]
Akimzhanov, A., Krenacs, L., Schlegel, T., Klein-Hessling, S., Bagdi, E., Stelkovics, E., Kondo, E., Chuvpilo, S., Wilke, P., Avots, A., Gattenlohner, S., Muller-Hermelink, H.-K., Palmetshofer, A., Serfling, E. (2008). Epigenetic Changes and Suppression of the Nuclear Factor of Activated T Cell 1 (NFATC1) Promoter in Human Lymphomas with Defects in Immunoreceptor Signaling. Am. J. Pathol. 172: 215-224 [Abstract] [Full Text]
Gurda, G. T., Guo, L., Lee, S.-H., Molkentin, J. D., Williams, J. A. (2008). Cholecystokinin Activates Pancreatic Calcineurin-NFAT Signaling In Vitro and In Vivo. Mol. Biol. Cell 19: 198-206 [Abstract] [Full Text]
Yeo, H., Beck, L. H., Thompson, S. R., Farach-Carson, M. C., McDonald, J. M., Clemens, T. L., Zayzafoon, M. (2007). Conditional Disruption of Calcineurin B1 in Osteoblasts Increases Bone Formation and Reduces Bone Resorption. J. Biol. Chem. 282: 35318-35327 [Abstract] [Full Text]
Bush, C. R., Havens, J. M., Necela, B. M., Su, W., Chen, L., Yanagisawa, M., Anastasiadis, P. Z., Guerra, R., Luxon, B. A., Thompson, E. A. (2007). Functional Genomic Analysis Reveals Cross-talk between Peroxisome Proliferator-activated Receptor {gamma} and Calcium Signaling in Human Colorectal Cancer Cells. J. Biol. Chem. 282: 23387-23401 [Abstract] [Full Text]
Cho, Y.-Y., Yao, K., Bode, A. M., Bergen, H. R. III, Madden, B. J., Oh, S.-M., Ermakova, S., Kang, B. S., Choi, H. S., Shim, J.-H., Dong, Z. (2007). RSK2 Mediates Muscle Cell Differentiation through Regulation of NFAT3. J. Biol. Chem. 282: 8380-8392 [Abstract] [Full Text]
Yang, T. T. C., Suk, H. Y., Yang, X., Olabisi, O., Yu, R. Y. L., Durand, J., Jelicks, L. A., Kim, J.-Y., Scherer, P. E., Wang, Y., Feng, Y., Rossetti, L., Graef, I. A., Crabtree, G. R., Chow, C.-W. (2006). Role of Transcription Factor NFAT in Glucose and Insulin Homeostasis. Mol. Cell. Biol. 26: 7372-7387 [Abstract] [Full Text]
Ikeda, F., Nishimura, R., Matsubara, T., Hata, K., Reddy, S. V., Yoneda, T. (2006). Activation of NFAT Signal In Vivo Leads to Osteopenia Associated with Increased Osteoclastogenesis and Bone-Resorbing Activity. J. Immunol. 177: 2384-2390 [Abstract] [Full Text]
Kim, H. B., Kong, M., Kim, T. M., Suh, Y. H., Kim, W.-H., Lim, J. H., Song, J. H., Jung, M. H. (2006). NFATc4 and ATF3 Negatively Regulate Adiponectin Gene Expression in 3T3-L1 Adipocytes.. Diabetes 55: 1342-1352 [Abstract] [Full Text]
Dai, Y.-S., Xu, J., Molkentin, J. D. (2005). The DnaJ-Related Factor Mrj Interacts with Nuclear Factor of Activated T Cells c3 and Mediates Transcriptional Repression through Class II Histone Deacetylase Recruitment. Mol. Cell. Biol. 25: 9936-9948 [Abstract] [Full Text]
Glud, S. Z., Sorensen, A. B., Andrulis, M., Wang, B., Kondo, E., Jessen, R., Krenacs, L., Stelkovics, E., Wabl, M., Serfling, E., Palmetshofer, A., Pedersen, F. S. (2005). A tumor-suppressor function for NFATc3 in T-cell lymphomagenesis by murine leukemia virus. Blood 106: 3546-3552 [Abstract] [Full Text]
Asagiri, M., Sato, K., Usami, T., Ochi, S., Nishina, H., Yoshida, H., Morita, I., Wagner, E. F., Mak, T. W., Serfling, E., Takayanagi, H. (2005). Autoamplification of NFATc1 expression determines its essential role in bone homeostasis. JEM 202: 1261-1269 [Abstract] [Full Text]
Imamura, T., Imamura, C., Iwamoto, Y., Sandell, L. J. (2005). Transcriptional Co-activators CREB-binding Protein/p300 Increase Chondrocyte Cd-rap Gene Expression by Multiple Mechanisms Including Sequestration of the Repressor CCAAT/Enhancer-binding Protein. J. Biol. Chem. 280: 16625-16634 [Abstract] [Full Text]
Asai, M., Iwasaki, Y., Yoshida, M., Mutsuga-Nakayama, N., Arima, H., Ito, M., Takano, K., Oiso, Y. (2004). Nuclear Factor of Activated T Cells (NFAT) Is Involved in the Depolarization-Induced Activation of Growth Hormone-Releasing Hormone Gene Transcription in Vitro. Mol. Endocrinol. 18: 3011-3019 [Abstract] [Full Text]
Kiani, A., Habermann, I., Haase, M., Feldmann, S., Boxberger, S., Sanchez-Fernandez, M. A., Thiede, C., Bornhauser, M., Ehninger, G. (2004). Expression and regulation of NFAT (nuclear factors of activated T cells) in human CD34+ cells: down-regulation upon myeloid differentiation. J. Leukoc. Biol. 76: 1057-1065 [Abstract] [Full Text]
Patra, A. K., Na, S.-Y., Bommhardt, U. (2004). Active Protein Kinase B Regulates TCR Responsiveness by Modulating Cytoplasmic-Nuclear Localization of NFAT and NF-{kappa}B Proteins. J. Immunol. 172: 4812-4820 [Abstract] [Full Text]
Hirotani, H., Tuohy, N. A., Woo, J.-T., Stern, P. H., Clipstone, N. A. (2004). The Calcineurin/Nuclear Factor of Activated T Cells Signaling Pathway Regulates Osteoclastogenesis in RAW264.7 Cells. J. Biol. Chem. 279: 13984-13992 [Abstract] [Full Text]
Groth, R. D., Mermelstein, P. G. (2003). Brain-Derived Neurotrophic Factor Activation of NFAT (Nuclear Factor of Activated T-Cells)-Dependent Transcription: A Role for the Transcription Factor NFATc4 in Neurotrophin-Mediated Gene Expression. J. Neurosci. 23: 8125-8134 [Abstract] [Full Text]
Neal, J. W., Clipstone, N. A. (2003). A Constitutively Active NFATc1 Mutant Induces a Transformed Phenotype in 3T3-L1 Fibroblasts. J. Biol. Chem. 278: 17246-17254 [Abstract] [Full Text]
Horsley, V., Pavlath, G. K. (2003). Prostaglandin F2{alpha} stimulates growth of skeletal muscle cells via an NFATC2-dependent pathway. JCB 161: 111-118 [Abstract] [Full Text]
van Rooij, E., Doevendans, P. A., de Theije, C. C., Babiker, F. A., Molkentin, J. D., De Windt, L. J. (2002). Requirement of Nuclear Factor of Activated T-cells in Calcineurin-mediated Cardiomyocyte Hypertrophy. J. Biol. Chem. 277: 48617-48626 [Abstract] [Full Text]
Wilkins, B. J., De Windt, L. J., Bueno, O. F., Braz, J. C., Glascock, B. J., Kimball, T. F., Molkentin, J. D. (2002). Targeted Disruption of NFATc3, but Not NFATc4, Reveals an Intrinsic Defect in Calcineurin-Mediated Cardiac Hypertrophic Growth. Mol. Cell. Biol. 22: 7603-7613 [Abstract] [Full Text]
Tomita, M., Reinhold, M. I., Molkentin, J. D., Naski, M. C. (2002). Calcineurin and NFAT4 Induce Chondrogenesis. J. Biol. Chem. 277: 42214-42218 [Abstract] [Full Text]
Butler, N. S., Monick, M. M., Yarovinsky, T. O., Powers, L. S., Hunninghake, G. W. (2002). Altered IL-4 mRNA Stability Correlates with Th1 and Th2 Bias and Susceptibility to Hypersensitivity Pneumonitis in Two Inbred Strains of Mice. J. Immunol. 169: 3700-3709 [Abstract] [Full Text]
Porter, C. M., Clipstone, N. A. (2002). Sustained NFAT Signaling Promotes a Th1-Like Pattern of Gene Expression in Primary Murine CD4+ T Cells. J. Immunol. 168: 4936-4945 [Abstract] [Full Text]
Horsley, V., Pavlath, G. K. (2002). Nfat: ubiquitous regulator of cell differentiation and adaptation. JCB 156: 771-774 [Abstract] [Full Text]
Jorgensen, C, Noel, D, Gross, G (2002). Could inflammatory arthritis be triggered by progenitor cells in the joints?. Ann Rheum Dis 61: 6-9 [Abstract] [Full Text]
Scott, E. S., Malcomber, S., O'Hare, P. (2001). Nuclear Translocation and Activation of the Transcription Factor NFAT Is Blocked by Herpes Simplex Virus Infection. J. Virol. 75: 9955-9965 [Abstract] [Full Text]
Liu, J., Arai, K.-i., Arai, N. (2001). Inhibition of NFATx Activation by an Oligopeptide: Disrupting the Interaction of NFATx with Calcineurin. J. Immunol. 167: 2677-2687 [Abstract] [Full Text]
Horsley, V., Friday, B. B., Matteson, S., Kegley, K. M., Gephart, J., Pavlath, G. K. (2001). Regulation of the Growth of Multinucleated Muscle Cells by an Nfatc2-Dependent Pathway. JCB 153: 329-338 [Abstract] [Full Text]
Jorgensen, C, Noel, D, Apparailly, F, Sany, J (2001). Stem cells for repair of cartilage and bone: the next challenge in osteoarthritis and rheumatoid arthritis. Ann Rheum Dis 60: 305-309 [Full Text]
Neal, J. W., Clipstone, N. A. (2001). Glycogen Synthase Kinase-3 Inhibits the DNA Binding Activity of NFATc. J. Biol. Chem. 276: 3666-3673 [Abstract] [Full Text]
Plyte, S., Boncristiano, M., Fattori, E., Galvagni, F., Paccani, S. R., Majolini, M. B., Oliviero, S., Ciliberto, G., Telford, J. L., Baldari, C. T. (2001). Identification and Characterization of a Novel Nuclear Factor of Activated T-cells-1 Isoform Expressed in Mouse Brain. J. Biol. Chem. 276: 14350-14358 [Abstract] [Full Text]
Tye, A. J., Ghebrehiwet, B., Guo, N., Sastry, K. N., Chow, B. K. C., Peerschke, E. I. B., Lim, B.-L. (2001). The Human gC1qR/p32 Gene, C1qBP. GENOMIC ORGANIZATION AND PROMOTER ANALYSIS. J. Biol. Chem. 276: 17069-17075 [Abstract] [Full Text]
Horsley, V., Pavlath, G. K. (2002). Nfat: ubiquitous regulator of cell differentiation and adaptation. JCB 156: 771-774 [Abstract] [Full Text]