title: MIP-1 gamma promotes receptor-activator-of-NF-kappa-B-ligand-induced osteoclast formation and survival.
abstract: 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-1 gamma, a C-C chemokine family member, on receptor activator of NF-kappa B ligand (RANKL)-stimulated osteoclast differentiation, survival, and activation. RANKL induced osteoclasts to dramatically increase production of MIP-1 gamma and to also express the MIP-1 gamma receptor CCR1, but had only minor effects on the related C-C chemokines MIP-1 alpha and RANTES. Neutralization of MIP-1 gamma 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-1 gamma or RANKL, both of which increased NF-kappa B activation in osteoclasts. Neutralization studies showed that the prosurvival effect of RANKL was in part dependent on its ability to induce MIP-1 gamma. Finally, osteoclast activation for bone resorption was stimulated by MIP-1 gamma. Taken together, these results demonstrate that MIP-1 gamma plays an important role in the differentiation and survival of osteoclasts, most likely via an autocrine pathway.
authors.affiliation: Department of Cytokine Biology, Forsyth Institute, Boston, MA 02115, USA.
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Okamatsu
authors.forename: David
authors.initials: D
authors.lastname: Kim
authors.forename: Ricardo
authors.initials: R
authors.lastname: Battaglino
authors.forename: Hajime
authors.initials: H
authors.lastname: Sasaki
authors.forename: Ulrike
authors.initials: U
authors.lastname: Späte
authors.forename: Philip
authors.initials: P
authors.lastname: Stashenko
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D001862:Bone Resorption / Q000503:physiopathology*; D002352:Carrier Proteins / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival; D002478:Cells, Cultured / Q000187:drug effects; D019742:Chemokines, CC / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D002352:Carrier Proteins; C095218:Ccl9 protein, mouse; C515301:Ccr1 protein, mouse; D019742:Chemokines, CC; D019402:Macrophage Inflammatory Proteins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D016173:Macrophage Colony-Stimulating Factor