Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 106, Issue 12, Pages 1481-1488Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI11176
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Funding
- NIAMS NIH HHS [R01 AR032788, AR07033, R01 AR046523, R37 AR046523, AR32788, T32 AR007033, R01 AR046852, AR46523] Funding Source: Medline
- NIDDK NIH HHS [R01 DK027726] Funding Source: Medline
- NIGMS NIH HHS [T32 GM007200] Funding Source: Medline
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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-kappaD and stress-activated protein kinase/c-Jun NH2-terminal kinase activity, two signaling pathways essential for osteoclastogenesis. In vivo administration of TNF-alpha prompts robust osteoclast formation in chimeric animals in which beta -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.
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