M-CSF mediates TNF-induced inflammatory osteolysis

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

Research output: Contribution to journalArticle

190 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3418-3427
Number of pages10
JournalJournal of Clinical Investigation
Volume115
Issue number12
DOIs
StatePublished - Dec 1 2005
Externally publishedYes

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Osteolysis
Macrophage Colony-Stimulating Factor
Stromal Cells
Osteoclasts
Macrophage Colony-Stimulating Factor Receptors
Tumor Necrosis Factor Receptors
Cytokines
Cytokine Receptors
Bone Resorption
Osteogenesis
Arthritis
Macrophages
Gene Expression
Bone and Bones

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Kitaura, H., Zhou, P., Kim, H. J., Novack, D. V., Ross, F. P., & Teitelbaum, S. L. (2005). M-CSF mediates TNF-induced inflammatory osteolysis. Journal of Clinical Investigation, 115(12), 3418-3427. https://doi.org/10.1172/JCI26132

M-CSF mediates TNF-induced inflammatory osteolysis. / Kitaura, Hideki; Zhou, Ping; Kim, Hyun Ju; Novack, Deborah V.; Ross, F. Patrick; Teitelbaum, Steven L.

In: Journal of Clinical Investigation, Vol. 115, No. 12, 01.12.2005, p. 3418-3427.

Research output: Contribution to journalArticle

Kitaura, H, Zhou, P, Kim, HJ, Novack, DV, Ross, FP & Teitelbaum, SL 2005, 'M-CSF mediates TNF-induced inflammatory osteolysis', Journal of Clinical Investigation, vol. 115, no. 12, pp. 3418-3427. https://doi.org/10.1172/JCI26132
Kitaura H, Zhou P, Kim HJ, Novack DV, Ross FP, Teitelbaum SL. M-CSF mediates TNF-induced inflammatory osteolysis. Journal of Clinical Investigation. 2005 Dec 1;115(12):3418-3427. https://doi.org/10.1172/JCI26132
Kitaura, Hideki ; Zhou, Ping ; Kim, Hyun Ju ; Novack, Deborah V. ; Ross, F. Patrick ; Teitelbaum, Steven L. / M-CSF mediates TNF-induced inflammatory osteolysis. In: Journal of Clinical Investigation. 2005 ; Vol. 115, No. 12. pp. 3418-3427.
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