Curcumin (diferuloylmethane) inhibits receptor activator of NF-kappa B ligand-induced NF-kappa B activation in osteoclast precursors and suppresses osteoclastogenesis

J Immunol. 2004 May 15;172(10):5940-7. doi: 10.4049/jimmunol.172.10.5940.

Abstract

Numerous studies have indicated that inflammatory cytokines play a major role in osteoclastogenesis, leading to the bone resorption that is frequently associated with cancers and other diseases. Gene deletion studies have shown that receptor activator of NF-kappaB ligand (RANKL) is one of the critical mediators of osteoclastogenesis. How RANKL mediates osteoclastogenesis is not fully understood, but an agent that suppresses RANKL signaling has potential to inhibit osteoclastogenesis. In this report, we examine the ability of curcumin (diferuloylmethane), a pigment derived from turmeric, to suppress RANKL signaling and osteoclastogenesis in RAW 264.7 cells, a murine monocytic cell line. Treatment of these cells with RANKL activated NF-kappaB, and preexposure of the cells to curcumin completely suppressed RANKL-induced NF-kappaB activation. Curcumin inhibited the pathway leading from activation of IkappaBalpha kinase and IkappaBalpha phosphorylation to IkappaBalpha degradation. RANKL induced osteoclastogenesis in these monocytic cells, and curcumin inhibited both RANKL- and TNF-induced osteoclastogenesis and pit formation. Curcumin suppressed osteoclastogenesis maximally when added together with RANKL and minimally when it was added 2 days after RANKL. Whether curcumin inhibits RANKL-induced osteoclastogenesis through suppression of NF-kappaB was also confirmed independently, as RANKL failed to activate NF-kappaB in cells stably transfected with a dominant-negative form of IkappaBalpha and concurrently failed to induce osteoclastogenesis. Thus overall these results indicate that RANKL induces osteoclastogenesis through the activation of NF-kappaB, and treatment with curcumin inhibits both the NF-kappaB activation and osteoclastogenesis induced by RANKL.

Publication types

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

MeSH terms

  • Animals
  • Bone Marrow Cells / cytology
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / physiology*
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology
  • Cell Line
  • Coated Pits, Cell-Membrane / drug effects
  • Coated Pits, Cell-Membrane / metabolism
  • Curcumin / pharmacology*
  • Enzyme Inhibitors / pharmacology
  • Growth Inhibitors / pharmacology*
  • I-kappa B Kinase
  • I-kappa B Proteins / antagonists & inhibitors
  • I-kappa B Proteins / metabolism
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Membrane Glycoproteins / antagonists & inhibitors
  • Membrane Glycoproteins / physiology*
  • Mice
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism*
  • Osteoclasts / cytology
  • Osteoclasts / drug effects
  • Osteoclasts / enzymology
  • Osteoclasts / metabolism*
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Stem Cells / cytology
  • Stem Cells / drug effects
  • Stem Cells / enzymology
  • Stem Cells / metabolism*

Substances

  • Carrier Proteins
  • Enzyme Inhibitors
  • Growth Inhibitors
  • I-kappa B Proteins
  • Membrane Glycoproteins
  • NF-kappa B
  • Nfkbia protein, mouse
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Tnfrsf11a protein, mouse
  • Tnfsf11 protein, mouse
  • NF-KappaB Inhibitor alpha
  • Protein-Serine-Threonine Kinases
  • Chuk protein, mouse
  • I-kappa B Kinase
  • Ikbkb protein, mouse
  • Ikbke protein, mouse
  • Curcumin