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
First Page
1481
Last Page
1488
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.
Recommended Citation
Lam J,
Takeshita S,
Barker JE,
Kanagawa O,
Ross FP,
Teitelbaum SL.
TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest 2000 Dec; 106(12):1481-8.