Title

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

Document Type

Article

Publication Date

2000

Keywords

Bone-Marrow-Transplantation, Carrier-Proteins, Cell-Differentiation, Cells-Cultured, Drug-Synergism, Enzyme-Activation, Flow-Cytometry, Histocytochemistry, Macrophages, Membrane-Glycoproteins, Mice, Mitogen-Activated-Protein-Kinases, NF-kappa-B, Osteoclasts, Stem-Cells, SUPPORT-NON-U-S-GOVT, SUPPORT-U-S-GOVT-P-H-S, Tumor-Necrosis-Factor

JAX Source

J Clin Invest 2000 Dec; 106(12):1481-8.

Grant

AR07033/AR/NIAMS, AR32788/AR/NIAMS, AR46523/AR/NIAMS, etal

Abstract

While TNF-alpha is pivotal to the pathogenesis of inflammatory osteolysis, the means by which it recruits osteoclasts and promotes bone destruction are unknown. We find that a pure population of murine osteoclast precursors fails to undergo osteoclastogenesis when treated with TNF-alpha alone. In contrast, the cytokine dramatically stimulates differentiation in macrophages primed by less than one percent of the amount of RANKL (ligand for the receptor activator of NF-kappaB) required to induce osteoclast formation. Mirroring their synergistic effects on osteoclast differentiation, TNF-alpha and RANKL markedly potentiate NF-kappaB and stress-activated protein kinase/c-Jun NH(2)-terminal kinase activity, two signaling pathways essential for osteoclastogenesis. In vivo administration of TNF-alpha prompts robust osteoclast formation in chimeric animals in which ss-galactosidase positive, TNF-responsive macrophages develop within a TNF-nonresponsive stromal environment. Thus, while TNF-alpha alone does not induce osteoclastogenesis, it does so both in vitro and in vivo by directly targeting macrophages within a stromal environment that expresses permissive levels of RANKL. Given the minuscule amount of RANKL sufficient to synergize with TNF-alpha to promote osteoclastogenesis, TNF-alpha appears to be a more convenient target in arresting inflammatory osteolysis.

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