NFAT and Osterix cooperatively regulate bone formation.
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 system. Calcineurin inhibitors FK506 and cyclosporin A inhibit nuclear factor of activated T cells (NFAT) activity and induce strong immunosuppression. Among NFAT proteins, NFATc1 is crucial for the differentiation of bone-resorbing osteoclasts. 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 Osterix-dependent activation of the Col1a1 (encoding type I collagen) promoter, but not Runx2-dependent activation of the Bglap1 (encoding osteocalcin) promoter. 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.
Koga
Takako
T
Department of Cell Signaling, Graduate School, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan. taka.csi@tmd.ac.jp
Matsui
Yuichi
Y
Asagiri
Masataka
M
Kodama
Tatsuhiko
T
de Crombrugghe
Benoit
B
Nakashima
Kazuhisa
K
Takayanagi
Hiroshi
H
D000818:Animals; D001846:Bone Development / Q000502:physiology*; D065095:Calcineurin Inhibitors; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D047468:Immunoprecipitation; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008156:Luciferases; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000076182:Sp7 Transcription Factor; D016559:Tacrolimus / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism*
D065095:Calcineurin Inhibitors; D017931:DNA Primers; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; D008156:Luciferases; D016559:Tacrolimus