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TNF-α induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand
Jonathan Lam, … , F. Patrick Ross, Steven L. Teitelbaum
Jonathan Lam, … , F. Patrick Ross, Steven L. Teitelbaum
Published December 15, 2000
Citation Information: J Clin Invest. 2000;106(12):1481-1488. https://doi.org/10.1172/JCI11176.
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TNF-α induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand

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Abstract

While TNF-α 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-α 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-κB) required to induce osteoclast formation. Mirroring their synergistic effects on osteoclast differentiation, TNF-α and RANKL markedly potentiate NF-κB and stress-activated protein kinase/c-Jun NH2-terminal kinase activity, two signaling pathways essential for osteoclastogenesis. In vivo administration of TNF-α prompts robust osteoclast formation in chimeric animals in which β-galactosidase positive, TNF-responsive macrophages develop within a TNF-nonresponsive stromal environment. Thus, while TNF-α 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-α to promote osteoclastogenesis, TNF-α appears to be a more convenient target in arresting inflammatory osteolysis.

Authors

Jonathan Lam, Sunao Takeshita, Jane E. Barker, Osami Kanagawa, F. Patrick Ross, Steven L. Teitelbaum

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Figure 2

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Purified myeloid cells fail to differentiate into osteoclasts in respons...
Purified myeloid cells fail to differentiate into osteoclasts in response to TNF-α. Cells, as characterized in Figure 1, were cultured with 10 ng/ml M-CSF plus (a) 1 ng/ml, (b) 2 ng/ml, (c) 5 ng/ml, (d) 10 ng/ml, (e) 20 ng/ml, (f) 40 ng/ml, (g) 80 ng/ml, and (h) 160 ng/ml TNF-α. Cells were stained for TRAP activity after 7 days. No multinucleated or TRAP-expressing cells are evident.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 4 patents
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