M-CSF mediates TNF-induced inflammatory osteolysis
Hideki Kitaura, Ping Zhou, Hyun-Ju Kim, Deborah V. Novack, F. Patrick Ross, Steven L. Teitelbaum
Hideki Kitaura, Ping Zhou, Hyun-Ju Kim, Deborah V. Novack, F. Patrick Ross, Steven L. Teitelbaum
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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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Figure 1

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Macrophage and stromal cell responsivity to TNF-α are required for optim...
Macrophage and stromal cell responsivity to TNF-α are required for optimal TNF-α–induced osteoclastogenesis in vivo. (A) Histological sections of calvaria excised from WT to WT (WT→WT), WT to KO, KO to WT, and KO to KO mice after 5 daily supracalvarial injections of increasing doses of TNF-α were stained for TRAP activity (red reaction product). Magnification, ×40. (B) The percentage of BM interface covered by osteoclasts was histomorphometrically determined in specimens derived from WT to WT, KO to WT, WT to KO, and KO to KO mice. *P < 0.01 compared with KO to KO mice. n = 3 mice per group.