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M-CSF mediates TNF-induced inflammatory osteolysis
Hideki Kitaura, … , F. Patrick Ross, Steven L. Teitelbaum
Hideki Kitaura, … , F. Patrick Ross, Steven L. Teitelbaum
Published December 1, 2005
Citation Information: J Clin Invest. 2005;115(12):3418-3427. https://doi.org/10.1172/JCI26132.
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Research Article Bone biology Article has an altmetric score of 9

M-CSF mediates TNF-induced inflammatory osteolysis

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Abstract

TNF-α is the dominant cytokine in inflammatory osteolysis. Using mice whose BM stromal cells and osteoclast precursors are chimeric for the presence of TNF receptors, we found that both cell types mediated the cytokine’s osteoclastogenic properties. The greater contribution was made, however, by stromal cells that express the osteoclastogenic cytokine M-CSF. TNF-α stimulated M-CSF gene expression, in vivo, only in the presence of TNF-responsive stromal cells. M-CSF, in turn, induced the key osteoclastogenic cytokine receptor, receptor activator of NF-κB (RANK), in osteoclast precursors. In keeping with the proproliferative and survival properties of M-CSF, TNF-α enhanced osteoclast precursor number only in the presence of stromal cells bearing TNF receptors. To determine the clinical relevance of these observations, we induced inflammatory arthritis in wild-type mice and treated them with a mAb directed against the M-CSF receptor, c-Fms. Anti–c-Fms mAb selectively and completely arrested the profound pathological osteoclastogenesis attending this condition, the significance of which is reflected by similar blunting of the in vivo bone resorption marker tartrate-resistant acid phosphatase 5b (TRACP 5b). Confirming that inhibition of the M-CSF signaling pathway targets TNF-α, anti–c-Fms also completely arrested osteolysis in TNF-injected mice with nominal effect on macrophage number. M-CSF and its receptor, c-Fms, therefore present as candidate therapeutic targets in states of inflammatory bone erosion.

Authors

Hideki Kitaura, Ping Zhou, Hyun-Ju Kim, Deborah V. Novack, F. Patrick Ross, Steven L. Teitelbaum

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Figure 3

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TNF-α–mediated increase in osteoclast precursor number in vivo requires ...
TNF-α–mediated increase in osteoclast precursor number in vivo requires cytokine-responsive stromal cells. The percentage of osteoclast precursors in BM recovered from WT to WT, WT to KO, KO to WT, and KO to KO mice after 5 daily injections of TNF-α (3 μg/day) or vehicle was determined by FACS, using FITC-conjugated anti-CD11b mAb (solid line) and FITC-conjugated isotype mAb (dotted line).

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

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Referenced in 58 patents
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