Bone Biology Bone Disease from a Placental Hypoxia Pathway

Nancy R. Gough

Science Signaling, AAAS, Washington, DC 20005, USA

Osteoclasts are cells of a hematopoetic lineage that resorb bone, and excessive activity of these cells can lead to low bone mass with an associated increased incidence of fractures. These cells are also implicated in disorders such as Paget's disease of the bone and multiple myeloma. Osteoclast differentiation requires the transcription factor AP-1, which is a heterodimer of a Jun family member and a Fos family member. Bozec et al. found that mice deficient for the Fos family member Fra-2, which is encoded by Fosl2, exhibited increased osteoclast size (giant osteoclasts), number, and activity. The expression and abundance of the leukemia inhibitory factor (LIF) receptor (LIFR) were also decreased in the bones of Fosl2 knockout mice. Chromatin immunoprecipitation experiments and reporter gene assays showed that LIF was a direct target of Fra-2 and Jun. Although no bone phenotype was reported for LIF knockout mice, Bozec et al. found that these mice had osteoclasts that were larger and more numerous with increased resorptive activity, which led to decreased bone volume. Fetal liver-derived osteoclast progenitor cells deficient in either Fra-2 or LIF did not differentiate in culture and exhibited increased apoptosis compared with wild-type cells; however, differentiation into osteoclasts was rescued by the addition of LIF. In vivo, the expression of Bcl-2, which encodes an antiapoptotic protein, was increased in the bones of Fra-2- or LIF-deficient animals. In vivo, osteoclasts were hypoxic and hypoxia-inducible factor-1 (HIF-1) was abundant, and the mRNA for PHD2 (prolyl hydroxylase domain 2 protein, which contributes to HIF-1 destabilization) was decreased, suggesting that hypoxia may contribute to the giant osteoclast phenotype. In culture, the Fra-2- or LIF-deficient osteoclast progenitors exhibited decreased Bcl-2 expression and increased cell death at 21% oxygen, and increased Bcl-2 expression and less cell death at 3% oxygen. Thus, the loss of LIF signaling appears to alter the sensitivity of the cells to oxygen. Surprisingly, selective knockout of Fra-2 in the macrophage-osteoclast lineage did not show bone phenotypes in vivo, but isolated progenitor cells failed to differentiate in the absence of additional LIF. Instead, it appeared that the Fra-2 knockout mice had impaired placental function, because LIF and LIFR and Phd2 expression were decreased in the placenta, and HIF-1 and its targets were increased. Thus, proper bone oxygenation in utero requires a functional LIF signaling axis that required Fra-2, and a similar pathway in the bone progenitors was required for proper oxygen responsiveness.

A. Bozec, L. Bakiri, A. Hoebertz, R. Eferl, A. F. Schilling, V. Komnenovic, H. Scheuch, M. Priemel, C. L. Stewart, M. Amling, E. F. Wagner, Osteoclast size is controlled by Fra-2 through LIF/LIF-receptor signalling and hypoxia. Nature 454, 221-225 (2008). [PubMed]