Tumor necrosis factor-α mediates RANK ligand stimulation of osteoclast differentiation by an autocrine mechanism

Authors

  • Wei Zou,

    1. The H Hubert Humphrey Center for Experimental Medicine and Cancer Research, The Hebrew University Faculty of Medicine, Jerusalem 91120, Israel
    Search for more papers by this author
  • Imad Hakim,

    1. The H Hubert Humphrey Center for Experimental Medicine and Cancer Research, The Hebrew University Faculty of Medicine, Jerusalem 91120, Israel
    Search for more papers by this author
  • Katharina Tschoep,

    1. Division of Clinical Pharmacology, Department of Medicine Ludwig-Maximilians-University, Munich 80336, Germany
    Search for more papers by this author
  • Stefan Endres,

    1. Division of Clinical Pharmacology, Department of Medicine Ludwig-Maximilians-University, Munich 80336, Germany
    Search for more papers by this author
  • Zvi Bar-Shavit

    Corresponding author
    1. The H Hubert Humphrey Center for Experimental Medicine and Cancer Research, The Hebrew University Faculty of Medicine, Jerusalem 91120, Israel
    • The H Hubert Humphrey Center for Experimental Medicine and Cancer Research, The Hebrew University Faculty of Medicine, P.O. Box 12272, Jerusalem 91120, Israel.
    Search for more papers by this author

  • This work was presented at the 22nd Annual meeting of the American Society for Bone and Mineral Research, Toronto, Ontario, Canada, September 22–26, 2000.

Abstract

Osteoblasts or bone marrow stromal cells are required as supporting cells for the in vitro differentiation of osteoclasts from their progenitor cells. Soluble receptor activator of nuclear factor-κB ligand (RANKL) in the presence of macrophage colony-stimulating factor (M-CSF) is capable of replacing the supporting cells in promoting osteoclastogenesis. In the present study, using Balb/c-derived cultures, osteoclast formation in both systems—osteoblast/bone-marrow cell co-cultures and in RANKL-induced osteoclastogenesis—was inhibited by antibody to tumor necrosis factor-α (TNF-α), and was enhanced by the addition of this cytokine. TNF-α itself promoted osteoclastogenesis in the presence of M-CSF. However, even at high concentrations of TNF-α the efficiency of this activity was much lower than the osteoclastogenic activity of RANKL. RANKL increased the level of TNF-α mRNA and induced TNF-α release from osteoclast progenitors. Furthermore, antibody to p55 TNF-α receptors (TNF receptors-1) (but not to p75 TNF-α receptors (TNF receptors-2) inhibited effectively RANKL- (and TNF-α() induced osteoclastogenesis. Anti-TNF receptors-1 antibody failed to inhibit osteoclastogenesis in C57BL/6-derived cultures. Taken together, our data support the hypothesis that in Balb/c, but not in C57BL/6 (strains known to differ in inflammatory responses and cytokine modulation), TNF-α is an autocrine factor in osteoclasts, promoting their differentiation, and mediates, at least in part, RANKL's induction of osteoclastogenesis. © 2001 Wiley-Liss, Inc.

Ancillary