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

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 fractures(1). Increased osteoclast size and numbers are also a hallmark of other disorders, such as Paget's disease and multiple myeloma(2). The protein c- Fos, a component of the AP- 1 transcription factor complex, is essential for osteoclast differentiation(3). 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 alpha ( HIF1 alpha) and Bcl- 2. Overexpression of Bcl- 2 is sufficient to induce giant osteoclasts in vivo, whereas Fra- 2 and LIF affect HIF1a 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.