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

M-CSF mediates TNF-induced inflammatory osteolysis

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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Anti–c-Fms mAb blocks TNF-α–induced osteoclastogenesis and bone resorpti...
Anti–c-Fms mAb blocks TNF-α–induced osteoclastogenesis and bone resorption in vivo. (A) Histological sections of calvariae excised from mice after 5 daily supracalvarial injections of TNF-α, with or without intraperitoneal injection of anti–c-Fms mAb, were stained for TRAP activity (red reaction product). Magnification, ×40. (B) The percentage of bone/BM interface covered by osteoclasts was histomorphometrically determined. (C) Circulating TRACP 5b levels were determined by ELISA. (D) Abundance of CD11b-positive osteoclast precursors in BM recovered from TNF-injected mice with (red line) or without (green line) anti–c-Fms mAb. The black line represents FITC-conjugated isotype mAb. The illustration is representative of 4 separate experiments. n = 4 in all groups. *P < 0.001 compared with TNF-α alone; #P < 0.001 compared with control.