TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand.

Abstract

While TNF-alpha 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-alpha 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-kappaB) required to induce osteoclast formation. Mirroring their synergistic effects on osteoclast differentiation, TNF-alpha and RANKL markedly potentiate NF-kappaB and stress-activated protein kinase/c-Jun NH(2)-terminal kinase activity, two signaling pathways essential for osteoclastogenesis. In vivo administration of TNF-alpha prompts robust osteoclast formation in chimeric animals in which ss-galactosidase positive, TNF-responsive macrophages develop within a TNF-nonresponsive stromal environment. Thus, while TNF-alpha 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-alpha to promote osteoclastogenesis, TNF-alpha appears to be a more convenient target in arresting inflammatory osteolysis.

• Authors: J Lam, S Takeshita, J E Barker, O Kanagawa, F P Ross, S L Teitelbaum
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 106 Issue 12 Pg. 1481-8 (Dec 2000) ISSN: 0021-9738 [Print] United States
• PMID: 11120755 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Carrier Proteins
• Membrane Glycoproteins
• NF-kappa B
• RANK Ligand
• Receptor Activator of Nuclear Factor-kappa B
• Tnfrsf11a protein, mouse
• Tnfsf11 protein, mouse
• Tumor Necrosis Factor-alpha
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinases

Topics

• Animals
• Bone Marrow Transplantation
• Carrier Proteins (pharmacology)
• Cell Differentiation (drug effects)
• Cells, Cultured
• Drug Synergism
• Enzyme Activation (drug effects)
• Flow Cytometry
• Histocytochemistry
• JNK Mitogen-Activated Protein Kinases
• Macrophages (cytology, drug effects, enzymology, metabolism)
• Membrane Glycoproteins (pharmacology)
• Mice
• Mitogen-Activated Protein Kinases (metabolism)
• NF-kappa B (metabolism)
• Osteoclasts (cytology, drug effects, enzymology, metabolism)
• RANK Ligand
• Receptor Activator of Nuclear Factor-kappa B
• Stem Cells (cytology, drug effects, enzymology, metabolism)
• Tumor Necrosis Factor-alpha (pharmacology)