The chemokine fractalkine (FKN) is produced by various cell types, including osteoblasts and endothelial cells in bone tissue, and signals through a sole receptor, CX3CR1, which is expressed on monocytes/macrophages, including osteoclast precursors (OCPs). However, the direct effects of FKN signaling on osteoclast lineage cells under homeostatic noninflammatory conditions remain unclear. Here, we report that FKN regulates mouse OCP survival and primes OCPs for subsequent osteoclast differentiation. Wild-type but not CX3CR1-deficient OCPs grown on immobilized FKN showed enhanced osteoclast formation following receptor activator of NF-κB ligand (RANKL) stimulation, with increased expression of osteoclast differentiation markers. Interestingly, the growth of OCPs on immobilized FKN increased the expression of Cx3cr1 and Tnfrsf11a (Rank) transcripts, but following RANKL stimulation, OCPs rapidly downregulated Cx3cr1 expression. Consistently, anti-FKN monoclonal antibody (mAb) treatment attenuated RANKL-induced osteoclast formation on immobilized FKN before, but not during, RANKL stimulation. CX3CR1 and RANK proteins were highly expressed on bone marrow-derived CD11bhigh CD115+ OCPs. Growth on immobilized FKN prior to RANKL stimulation also increased CD11bhigh CD115+ OCP number and their survival and differentiation potential. In a RANKL-based mouse model of bone loss, anti-FKN mAb pretreatment significantly inhibited RANKL-dependent bone loss. Thus, blocking the FKN-CX3CR1 axis could represent a therapeutic option in noninflammatory bone loss diseases.
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