Does TNF have anti-osteoclastogenic actions?
Tumor necrosis factor (TNF) is a pro-resorption agent that leads to bone degradation. Several mechanisms of action have been proposed to account for these effects: TNF directly inhibits osteoblast differentiation; TNF augments osteoclast formation by inducing stromal cells to increase expression of RANKL and macrophage colony-stimulating factor (M-CSF) and decrease that of osteoprotegerin (OPG); and TNF serves to synergize with pathways downstream of RANK to directly increase osteoclast differentiation. All of these actions in sum suggest that TNF dramatically induces osteopenia upon overexpression or injection. However, that the osteopenia seen with TNF is significantly milder than that seen in OPG-/- animals prompted a reevaluation of existing paradigms on TNF action. The hypothesis that TNF directly enhances osteoclast differentiation was tested by examining the effects of TNF on RANKL-induced osteoclast formation and marker expression. The data show that TNF decreased RANKL-induced expression of the osteoclast markers, TRAP and cathepsin K. Furthermore, the addition of 10-60 ng/mL TNF failed to significantly increase RANKL-induced osteoclast differentiation. Instead, data are presented to suggest that the pro-osteoclastogenic actions of TNF are mediated through increases in the number of available osteoclast precursors (macrophages).
Iqbal
Jameel
J
Department of Endocrinology (1055), Mount Sinai School of Medicine, One Gustave L. Levy Place New York, NY 10029, USA. jameel.iqbal@mssm.edu
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016173:Macrophage Colony-Stimulating Factor