MIP-1γ promotes receptor activator of NF-κB ligand-induced osteoclast formation and survival

Chemokines play an important role in immune and inflammatory responses by inducing migration and adhesion of leukocytes, and have also been reported to modulate osteoclast differentiation from hemopoietic precursor cells of the monocyte-macrophage lineage. In this study, we examined the effect of MIP-1gamma, a C-C chemokine family member, on receptor activator of NF-kappaB ligand (RANKL)-stimulated osteoclast differentiation, survival, and activation. RANKL induced osteoclasts to dramatically increase production of MIP-1gamma and to also express the MIP-1gamma receptor CCR1, but had only minor effects on the related C-C chemokines MIP-1alpha and RANTES. Neutralization of MIP-1gamma with specific Ab reduced RANKL-stimulated osteoclast differentiation by 60-70%. Mature osteoclasts underwent apoptosis within 24 h after removal of RANKL, as shown by increased caspase 3 activity and DNA fragmentation. Apoptosis was reduced by the addition of exogenous MIP-1gamma or RANKL, both of which increased NF-kappaB activation in osteoclasts. Neutralization studies showed that the prosurvival effect of RANKL was in part dependent on its ability to induce MIP-1gamma. Finally, osteoclast activation for bone resorption was stimulated by MIP-1gamma. Taken together, these results demonstrate that MIP-1gamma plays an important role in the differentiation and survival of osteoclasts, most likely via an autocrine pathway.