IL-34, in Synergy with RANK Ligand, Promotes Osteoclast Development through the CSF-1 Receptor

IL-34 is a newly identified cytokine that binds to the CSF-1 receptor (CSF-1R), promotes monocyte viability, and stimulates macrophage colony formation (Lin et al., 2008). Here we demonstrate that human IL-34 induced tyrosine phosphorylation of the CSF-1R in cells of a mouse MacCsf1r−/−.huCSF-1R macrophage line. MacCsf1r−/−.huCSF-1R cells were obtained by retroviral transduction of the human CSF-1R into cells of the MacCsf1r−/− macrophage line (Yu et al., 2008) derived from bone marrow macrophages isolated from a CSF-1R-deficient mouse. In addition, IL-34 stimulated the downstream signaling of ERK1/2 and the IL-34-induced phosphorylation of ERK1/2 was blocked by a CSF-1R-specific inhibitor. IL-34, in synergy with RANK ligand, promoted formation of tartrate resistant acid phosphatase (TRAP)-positive and multinucleated osteoclasts from monocytes in dose-dependent manner. The activity of IL-34 on osteoclast differentiation was inhibited by the soluble CSF-1R extracellular domain. Therefore, IL-34 functions as a new ligand of CSF-1R and participates in the regulation of osteoclast development.