The Journal of Experimental Medicine
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© 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. Rangera, Louis C. Gerstenfeldd, Jinxi Wangb, Tamiyo Kond,e, Hyunsu Baea, Ellen M. Gravallesec, Melvin J. Glimcherb, and Laurie H. Glimchera,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 factors regulate gene expression in lymphocytes and control cardiac valve formation. Here, we report that NFATp regulates chondrogenesis in the adult animal. In mice lacking NFATp, resident cells in the extraarticular connective tissues spontaneously differentiate to cartilage. These cartilage cells progressively differentiate and the tissue undergoes endochondral ossification, recapitulating the development of endochondral bone. Proliferation of already existing articular cartilage cells also occurs in some older animals. At both sites, neoplastic changes in the cartilage cells occur. Consistent with these data, NFATp expression is regulated in mesenchymal stem cells induced to differentiate along a chondrogenic pathway. Lack of NFATp in articular cartilage cells results in increased expression of cartilage markers, whereas overexpression of NFATp in cartilage cell lines extinguishes the cartilage phenotype. Thus, NFATp is a repressor of cartilage cell growth and differentiation and also has the properties of 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, cartilage oligomeric protein; EA, extraarticular cartilage cell line; GDF, growth/differentiation factor; HPRT, hypoxanthine phosphoribosyltransferase; MSC, mesenchymal stem cell; NFAT, nuclear factor of activated T cells; PTHrP, parathyroid hormone–related protein; RT, reverse transcription; wt, wild-type.

© 2000 The Rockefeller University Press


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