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

Hiroshi Takayanagi, Sunhwa Kim, Koichi Matsuo, Hiroshi Suzuki, Tomohiko Suzuki, Kojiro Sato, Taeko Yokochi, Hiromi Oda, Kozo Nakamura, Nobutaka Ida, Erwin F. Wagner and Tadatsugu Taniguchi ()
Additional contact information
Hiroshi Takayanagi: University of Tokyo
Sunhwa Kim: University of Tokyo
Koichi Matsuo: Research Institute of Molecular Pathology (IMP)
Hiroshi Suzuki: University of Tokyo
Tomohiko Suzuki: Toray Industries, Inc.
Kojiro Sato: University of Tokyo
Taeko Yokochi: University of Tokyo
Hiromi Oda: University of Tokyo
Kozo Nakamura: University of Tokyo
Nobutaka Ida: Toray Industries, Inc.
Erwin F. Wagner: Research Institute of Molecular Pathology (IMP)
Tadatsugu Taniguchi: University of Tokyo

Nature, 2002, vol. 416, issue 6882, 744-749

Abstract: 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.

Date: 2002
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DOI: 10.1038/416744a

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