Nature Medicine
11, 880 - 885 (2005)
Published online: 24 July 2005; | doi:10.1038/nm1270
NFAT and Osterix cooperatively regulate bone formationTakako Koga1, 6, Yuichi Matsui2, 3, Masataka Asagiri1, 6, Tatsuhiko Kodama3, Benoit de Crombrugghe4, Kazuhisa Nakashima5, 6
& Hiroshi Takayanagi1, 61
Department of Cell Signaling, Graduate School, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan, and SORST, Japan Science and Technology Agency (JST), Honcho 4-1-8, Kawaguchi, Saitama 332-0012, Japan. 2
Department of Surgery, Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan. 3
Department of Molecular Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Komaba 4-6-1, Meguro-ku, Tokyo 153-8904, Japan. 4
Department of Molecular Genetics, M.D. Anderson Cancer Center, University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. 5
Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Kanda-Surugadai 2-3-10, Chiyoda-ku, Tokyo 101-0062, Japan. 6
COE Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone.
Correspondence should be addressed to Hiroshi Takayanagi taka.csi@tmd.ac.jp Immunosuppressants are crucial in the prevention of detrimental immune reactions associated with allogenic organ transplantation, but they often cause adverse effects in a number of biological systems, including the skeletal system1,
2. Calcineurin inhibitors FK506 and cyclosporin A inhibit nuclear factor of activated T cells (NFAT) activity and induce strong immunosuppression3,
4,
5. Among NFAT proteins, NFATc1 is crucial for the differentiation of bone-resorbing osteoclasts6,
7. Here we show FK506 administration induces the reduction of bone mass despite a blockade of osteoclast differentiation. This reduction is caused by severe impairment of bone formation, suggesting that NFAT transcription factors also have an important role in the transcriptional program of osteoblasts. In fact, bone formation is inhibited in Nfatc1- and Nfatc2-deficient cells as well as in FK506-treated osteoblasts. Overexpression of NFATc1 stimulates Osterix8-dependent activation of the Col1a1 (encoding type I collagen) promoter, but not Runx2-dependent activation of the Bglap1 (encoding osteocalcin) promoter9. NFAT and Osterix form a complex that binds to DNA, and this interaction is important for the transcriptional activity of Osterix. Thus, NFAT and Osterix cooperatively control osteoblastic bone formation. These results may provide important insight into the management of post-transplantation osteoporosis as well as a new strategy for promoting bone regeneration in osteopenic disease.
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