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RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-β

Abstract

Osteoclasts are cells of monocyte/macrophage origin that erode bone matrix: regulation of their differentiation is central to the understanding of the pathogenesis and treatment of bone diseases such as osteoporosis1,2. Signalling by RANKL (receptor activator of NF-κB ligand), also known as Tnfsf11, is essential for the induction of osteoclast differentiation3,4,5, and it must be strictly regulated to maintain bone homeostasis. But it is not known whether RANKL signalling to the cell interior is linked to any regulatory mechanisms. Here we show that RANKL induces the interferon-β (IFN-β) gene in osteoclast precursor cells, and that IFN-β inhibits the differentiation by interfering with the RANKL-induced expression of c-Fos, an essential transcription factor for the formation of osteoclasts. This IFN-β gene induction mechanism is distinct from that induced by virus, and is dependent on c-Fos itself. Thus an autoregulatory mechanism operates—the RANKL-induced c-Fos induces its own inhibitor. The importance of this regulatory mechanism for bone homeostasis is emphasized by the observation that mice deficient in IFN-β signalling exhibit severe osteopenia (loss of bone mass) accompanied by enhanced osteoclastogenesis. Our study places the IFN-β system in a new context, and may offer a molecular basis for the treatment of bone diseases.

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Figure 1: Bone phenotype of mice deficient in IFN-α/β signalling.
Figure 2: Selective induction of IFN-β mRNA by RANKL and the function of IFN-β in vivo and in vitro.
Figure 3: IFN-β inhibits RANKL signalling by suppressing the c-Fos protein expression.
Figure 4: c-Fos-dependent induction of IFN-β by RANKL.
Figure 5: Therapeutic effect of IFN-β and its novel signalling cross-talk with RANKL.

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Acknowledgements

We thank H. Murayama and Kureha Chemical Industries for technical assistance, and E. Barsoumian, A. Bichl, M. Radolf, A. Takaoka, K. Honda, M. Asagiri, N. Hata, S. Muraki, M. Isobe, S. Kano and I. Kawai for discussion and assistance. This work was supported in part by a grant for Advanced Research on Cancer from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, a research fellowship of the Japan Society for the Promotion of Science for Young Scientists, Health Sciences Research Grants from the Ministry of Health and Welfare of Japan, the Japan Orthopaedics and Traumatology Foundation, and PRESTO, Japan Science and Technology Corporation.

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Correspondence to Tadatsugu Taniguchi.

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Takayanagi, H., Kim, S., Matsuo, K. et al. RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-β. Nature 416, 744–749 (2002). https://doi.org/10.1038/416744a

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