1. Research Institute of Molecular Pathology (I.M.P.), Dr. Bohr-Gasse 7, A-1030 Vienna, Austria
2. Center for Biomechanics and Skeletal Biology, Department of Trauma, Hand, and Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany
3. Developmental and Regenerative Biology Laboratory, Institute of Medical Biology (I.M.B.), 8A Biomedical Grove, #06-06 Immunos, 138648 Singapore
4. 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.).

Correspondence to: Erwin F. Wagner^1,4 Correspondence and requests for materials should be addressed to E.F.W. (Email: wagner@imp.ac.at or Email: ewagner@cnio.es).

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 1 (HIF1) and Bcl-2. Overexpression of Bcl-2 is sufficient to induce giant osteoclasts in vivo, whereas Fra-2 and LIF affect HIF1 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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