Abstract
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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Acknowledgements
We are grateful to T. W. Mak and L. Glimcher for providing Nfatc1−/− and Nfatc2−/− mice. We thank G. Karsenty, K. Imamura, M.A. Brown, RNAi Co., Ltd., and Fujisawa Pharmaceutical Co., Ltd. for providing plasmids and reagents. We also thank M. Noda, I. Morita, A. Izumi, T. Kohro, H. Murayama, T. Hongo, K. Sato, M. Shinohara, K. Nishikawa, H.J. Göber, S. Harumiya, A. Suematsu, Y. Kim, S. Ochi, M. Isobe, J. Hirooka, N. Kumasaki and I. Kawai for discussion and technical assistance. This work was supported in part by PRESTO and SORST programs of JST, grants for Genome Network Project from Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT), grants for the 21st century COE program, Grants-in-Aid for Scientific Research from Japan Society for the Promotion of Science and MEXT, Health Sciences Research Grants from the Ministry of Health, Labour and Welfare of Japan, grants from the Mitsubishi Foundation, the Kato Trust for Nambyo Research, Takeda Science Foundation, Daiwa Securities Health Foundation, the Naito Foundation, Kowa Life Science Foundation, Suzuken Memorial Foundation, Kato Memorial Bioscience Foundation, Inamori Foundation, Uehara Memorial Foundation and the Nakajima Foundation.
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Koga, T., Matsui, Y., Asagiri, M. et al. NFAT and Osterix cooperatively regulate bone formation. Nat Med 11, 880–885 (2005). https://doi.org/10.1038/nm1270
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DOI: https://doi.org/10.1038/nm1270
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