Cross-talk between the interleukin-6 and prostaglandin E(2) signaling systems results in enhancement of osteoclastogenesis through effects on the osteoprotegerin/receptor activator of nuclear factor-{kappa}B (RANK) ligand/RANK system

Endocrinology. 2005 Apr;146(4):1991-8. doi: 10.1210/en.2004-1167. Epub 2004 Dec 23.

Abstract

The osteoprotegerin (OPG)/receptor activator of nuclear factor-kappaB ligand (RANKL)/receptor activator of nuclear factor-kappaB (RANK) system is the dominant and final mediator of osteoclastogenesis. Abnormalities of this system have been implicated in the pathogenesis of many skeletal diseases. Cyclooxygenase (COX)-2 and prostaglandin (PG)E(2), a major eicosanoid product of the COX-2-catalyzed pathway, play key roles in normal bone tissue remodeling. PGE(2) exerts its actions by binding and activating the E series of prostaglandin (EP) receptor. Activation of EP(2) and EP(4) receptors is associated with PGE(2)-induced osteoclast differentiation. IL-6, a major proinflammatory cytokine, has also been reported to induce osteoclast differentiation. Although interactions between the COX-2/PGE(2) and IL-6 systems have been described in bone cells, the mechanisms underlying these cooperative signaling pathways and the possible involvement of the OPG/RANKL/RANK system have not been fully elucidated. We demonstrate that COX-2, PGE(2), and IL-6 stimulate osteoblast growth and osteoclast differentiation. Effects on osteoclast differentiation, particularly with IL-6, were most marked when osteoclast precursor cells were grown in coculture with osteoblasts, indicating a possible role of the RANK/RANKL/OPG system. COX-2 and PGE(2) stimulated osteoclastogenesis through inhibition of OPG secretion, stimulation of RANKL production by osteoblasts, and up-regulation of RANK expression in osteoclasts. PGE(2) stimulated IL-6 secretion by bone cells, whereas COX-2 inhibitors decreased this same parameter. IL-6, in turn, increased PGE(2) secretion, COX-2, and EP receptor subtype expression in bone cells. Finally, IL-6 was the mediator of PGE(2)-induced suppression of OPG production by osteoblasts. These findings provide evidence for cross-talk between the PGE(2) and IL-6 signaling enhance osteoclast differentiation via effects on the OPG/RANKL/RANK system in bone cells.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Carrier Proteins / physiology*
  • Cell Line
  • Dinoprostone / pharmacology*
  • Glycoproteins / physiology*
  • Interleukin-6 / biosynthesis
  • Interleukin-6 / pharmacology*
  • Membrane Glycoproteins / physiology*
  • Mice
  • Osteoblasts / drug effects
  • Osteoblasts / physiology
  • Osteoclasts / drug effects
  • Osteoclasts / physiology*
  • Osteogenesis / drug effects*
  • Osteoprotegerin
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Receptors, Tumor Necrosis Factor
  • Signal Transduction / physiology*

Substances

  • Carrier Proteins
  • Glycoproteins
  • Interleukin-6
  • Membrane Glycoproteins
  • Osteoprotegerin
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Tumor Necrosis Factor
  • Tnfrsf11a protein, mouse
  • Tnfrsf11b protein, mouse
  • Tnfsf11 protein, mouse
  • Dinoprostone