Inhibition of RANKL-mediated osteoclast differentiation by selective TRAF6 decoy peptides

Biochem Biophys Res Commun. 2007 Aug 3;359(3):510-5. doi: 10.1016/j.bbrc.2007.05.151. Epub 2007 May 30.

Abstract

RANK and RANKL are essential mediators of osteoclastogenesis. RANK interacts with members of the tumor necrosis factor receptor-associated factor (TRAF) family, of which TRAF6 is the critical signaling molecule. We identified a unique TRAF6-binding motif in RANK, which was subsequently co-crystallized with TRAF6 revealing distinct molecular interactions. A cell-permeable TRAF6 decoy peptide (T6DP) was shown to specifically target TRAF6 and inhibit RANKL-mediated signaling. In this study, we identified a core motif for binding to TRAF6 by generating a series of deletion mutants linked via palmitate as a means to internalize the peptide, thus making a smaller scaffold for intracellular delivery. The core motif of RKIPTEDEY inhibited RANKL-mediated osteoclastogenesis and bone resorption. In contrast, TRAF2/5 decoy peptides appeared to have no affect. Thus, disruption of the RANK-TRAF6 interaction may prove useful as a novel target for the development of a small molecule therapeutic agent for the treatment of bone-related diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Bone Resorption / pathology
  • Bone Resorption / prevention & control
  • Cell Differentiation / drug effects*
  • Cells, Cultured
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Osteoclasts / cytology*
  • Osteoclasts / drug effects
  • Osteoclasts / metabolism
  • Peptide Fragments / chemical synthesis
  • Peptide Fragments / chemistry
  • Peptide Fragments / pharmacology*
  • Protein Binding
  • RANK Ligand / pharmacology*
  • TNF Receptor-Associated Factor 2 / chemical synthesis
  • TNF Receptor-Associated Factor 2 / chemistry
  • TNF Receptor-Associated Factor 2 / pharmacology
  • TNF Receptor-Associated Factor 5 / chemical synthesis
  • TNF Receptor-Associated Factor 5 / chemistry
  • TNF Receptor-Associated Factor 5 / pharmacology
  • TNF Receptor-Associated Factor 6 / chemistry
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / metabolism
  • TNF Receptor-Associated Factor 6 / pharmacology*
  • Time Factors

Substances

  • Peptide Fragments
  • RANK Ligand
  • TNF Receptor-Associated Factor 2
  • TNF Receptor-Associated Factor 5
  • TNF Receptor-Associated Factor 6