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

J Cell Biochem. 2001 Jun 26-Jul 25;83(1):70-83. doi: 10.1002/jcb.1202.

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-kappaB 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-alpha (TNF-alpha), and was enhanced by the addition of this cytokine. TNF-alpha itself promoted osteoclastogenesis in the presence of M-CSF. However, even at high concentrations of TNF-alpha the efficiency of this activity was much lower than the osteoclastogenic activity of RANKL. RANKL increased the level of TNF-alpha mRNA and induced TNF-alpha release from osteoclast progenitors. Furthermore, antibody to p55 TNF-alpha receptors (TNF receptors-1) (but not to p75 TNF-alpha receptors (TNF receptors-2) inhibited effectively RANKL- (and TNF-alpha() 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-alpha is an autocrine factor in osteoclasts, promoting their differentiation, and mediates, at least in part, RANKL's induction of osteoclastogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Phosphatase / metabolism
  • Animals
  • Animals, Newborn
  • Antibodies / immunology
  • Antibodies / pharmacology
  • Autocrine Communication / drug effects*
  • Blotting, Western
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / metabolism
  • Carrier Proteins / metabolism*
  • Cell Differentiation / drug effects*
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Male
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Osteoclasts / cytology*
  • Osteoclasts / drug effects*
  • RANK Ligand
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptors, Tumor Necrosis Factor / antagonists & inhibitors
  • Receptors, Tumor Necrosis Factor / immunology
  • Receptors, Tumor Necrosis Factor / metabolism
  • Stem Cells / cytology
  • Stem Cells / drug effects
  • Stem Cells / metabolism
  • Time Factors
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Antibodies
  • Carrier Proteins
  • Membrane Glycoproteins
  • RANK Ligand
  • RNA, Messenger
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptors, Tumor Necrosis Factor
  • Tnfrsf11a protein, mouse
  • Tnfsf11 protein, mouse
  • Tumor Necrosis Factor-alpha
  • Acid Phosphatase