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Osteoclast size is controlled by Fra-2 through LIF/LIF-receptor signalling and hypoxia

Nature volume 454, pages 221–225 (2008)Cite this article

Abstract

Osteoclasts are multinucleated haematopoietic cells that resorb bone. Increased osteoclast activity causes osteoporosis, a disorder resulting in a low bone mass and a high risk of fractures1. Increased osteoclast size and numbers are also a hallmark of other disorders, such as Paget’s disease and multiple myeloma2. The protein c-Fos, a component of the AP-1 transcription factor complex, is essential for osteoclast differentiation3. Here we show that the Fos-related protein Fra-2 controls osteoclast survival and size. The bones of Fra-2-deficient newborn mice have giant osteoclasts, and signalling through leukaemia inhibitory factor (LIF) and its receptor is impaired. Similarly, newborn animals lacking LIF have giant osteoclasts, and we show that LIF is a direct transcriptional target of Fra-2 and c-Jun. Moreover, bones deficient in Fra-2 and LIF are hypoxic and express increased levels of hypoxia-induced factor 1α (HIF1α) and Bcl-2. Overexpression of Bcl-2 is sufficient to induce giant osteoclasts in vivo, whereas Fra-2 and LIF affect HIF1α through transcriptional modulation of the HIF prolyl hydroxylase PHD2. This pathway is operative in the placenta, because specific inactivation of Fra-2 in the embryo alone does not cause hypoxia or the giant osteoclast phenotype. Thus placenta-induced hypoxia during embryogenesis leads to the formation of giant osteoclasts in young pups. These findings offer potential targets for the treatment of syndromes associated with increased osteoclastogenesis.

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Figure 1: Giant osteoclasts and decreased LIF/LIFR signalling in pups lacking Fra-2 ( Fosl2).
Figure 2: LIF inactivation or Bcl-2 overexpression leads to giant osteoclasts.
Figure 3: Hypoxia in Fra-2-deficient and LIF-deficient long bones.
Figure 4: A placental origin for the giant osteoclast defect.

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Acknowledgements

We thank E. Schipani for providing protocols and reagents for hypoxia stainings; A. Schleiffer and A. Souabni for experimental advice; and A. Grigoriadis, C. Hartmann, T. Jenuwein, R. Johnson and M. Sibilia for numerous suggestions and critical reading of the manuscript. The Institute of Molecular Pathology is funded by Boehringer Ingelheim and this work was supported by the Austrian Industrial Research Promotion Fund. L.B. is partly funded by the NoE Cells into Organs (LSHM-CT-2003-504468). A.H. was the recipient of an EMBO and Marie Curie long-term fellowship. M.A. is funded by the German Research Community (DFG).

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Author notes

  1. Aline Bozec, Latifa Bakiri, Robert Eferl & Erwin F. Wagner

    Present address: Present addresses: Spanish National Cancer Research Centre (C.N.I.O.), C/ Melchor Fernández Almagro, 3, E-28029 Madrid, Spain (A.B., L.B., E.F.W.); Ludwig Boltzmann Institute for Cancer Research, Währinger Strasse 13a, A-1090 Vienna, Austria (R.E.).,

Authors and Affiliations

  1. Research Institute of Molecular Pathology (I.M.P.), Dr. Bohr-Gasse 7, A-1030 Vienna, Austria,

    Aline Bozec, Latifa Bakiri, Astrid Hoebertz, Robert Eferl, Vukoslav Komnenovic, Harald Scheuch & Erwin F. Wagner

  2. Department of Trauma, Center for Biomechanics and Skeletal Biology, Hand, and Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany,

    Arndt F. Schilling, Matthias Priemel & Michael Amling

  3. Developmental and Regenerative Biology Laboratory, Institute of Medical Biology (I.M.B.), 8A Biomedical Grove, #06-06 Immunos, 138648 Singapore,

    Colin L. Stewart

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Correspondence to Erwin F. Wagner.

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Bozec, A., Bakiri, L., Hoebertz, A. et al. Osteoclast size is controlled by Fra-2 through LIF/LIF-receptor signalling and hypoxia. Nature 454, 221–225 (2008). https://doi.org/10.1038/nature07019

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