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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 9

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TNF-α directly induces myeloid cells to differentiate into committed ost...
TNF-α directly induces myeloid cells to differentiate into committed osteoclast precursors and mature osteoclasts in vivo, irrespective of the capacity of stromal cells to respond to the cytokine. Chimeric animals were created by bone marrow transplantation in which β-galactosidase–positive osteoclast precursors exist within the stromal environments of TNFR-deficient animals or their TNFR-heterozygous littermates. Following engraftment, the animals were depleted of T cells and administered 150 μg/kg/day TNF-α or vehicle for 5 days by subcutaneous injection. (a) Equal numbers of whole marrow cells were then cultured ex vivo for 7 days in osteoclastogenic conditions, and stained for TRAP and β-galactosidase activity in combination. (b) Decalcified sections of long bones, representative of data from six chimeric animals, were stained for TRAP activity (red reaction product) (left panels, ×100; right panels, ×250).

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

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Referenced in 4 patents
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