TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand

While TNF-alpha is pivotal to the pathogenesis of inflammatory osteolysis, the means by which it recruits osteoclasts and promotes bone destruction ar e unknown. We find that a pure population of murine osteoclast precursors f ails to undergo osteoclastogenesis when treated with TNF-alpha alone. In co ntrast, the cytokine dramatically stimulates differentiation in macrophages primed by less than one percent of the amount of RANKL (ligand for the rec eptor activator of NF-kappaB) required to induce osteoclast formation. Mirr oring their synergistic effects on osteoclast differentiation, TNF-alpha an d RANKL markedly potentiate NF-kappaD and stress-activated protein kinase/c -Jun NH2-terminal kinase activity, two signaling pathways essential for ost eoclastogenesis. In vivo administration of TNF-alpha prompts robust osteocl ast formation in chimeric animals in which beta -galactosidase positive, TN F-responsive macrophages develop within a TNF-nonresponsive stromal environ ment. Thus, while TNF-alpha alone does not induce osteoclastogenesis, it do es so both in vitro and in vivo by directly targeting macrophages within a stromal environment that expresses permissive levels of RANKL. Given the mi nuscule amount of RANKL sufficient to synergize with TNF-alpha. to promote osteoclastogenesis, TNF-alpha appears to be a more convenient target in arr esting inflammatory osteolysis.