Bifurcation of osteoclasts and dendritic cells from common progenitors

Osteoclasts and dendritic cells are derived from monocyte/macrophage precur sor cells; however, how their lineage commitment is regulated is unknown. T his study investigated the differentiation pathways of osteoclasts and dend ritic cells from common precursor cells at the single-cell level. Osteoclas togenesis induced by macrophage colony-stimulating factor (M-CSF) and recep tor activator of nuclear factor-kappaB ligand (RANKL) or tumor necrosis fac tor-alpha (TNF-alpha) is completely inhibited by addition of granulocyte-ma crophage colony-stimulating factor (GM-CSF) or interleukin-3 at early stage s of differentiation. GM-CSF-treated cells express both c-Fms and RANK and also low levels of CD11c and DEC205, which are detected on dendritic cells. Addition of GM-CSF also reduces expression of both c-Fos and Fra-1, which is an important event for inhibition of osteoclastogenesis. Overexpression of c-Fos by retroviral infection or induction in transgenic mice can rescue a failure in osteoclast differentiation even in the presence of GM-CSF. By contrast, differentiation into dendritic cells is inhibited by M-CSF, indi cating that M-CSF and GMCSF reciprocally regulate the differentiation of bo th lineages. Dendritic cell maturation is also inhibited when c-Fos is expr essed at an early stage of differentiation. Taken together, these findings suggest that c-Fos is a key mediator of the lineage commitment between oste oclasts and dendritic cells. The lineage determination of osteoclast progen itors seen following GM-CSF treatment functions through the regulation of c -Fos expression. (Blood. 2001;98:2544-2554) (C) 2001 by The American Societ y of Hematology.