A TNF receptor loop peptide mimic blocks RANK ligand-induced signaling, bone resorption, and bone loss

Kazuhiro Aoki, Hiroaki Saito, Cecile Itzstein, Masaji Ishiguro, Tatsuya Shibata, Roland Blanque, Anower Hussain Mian, Mariko Takahashi, Yoshifumi Suzuki, Masako Yoshimatsu, Akira Yamaguchi, Pierre Deprez, Patrick Mollat, Ramachandran Murali, Keiichi Ohya, William C Horne, Roland Baron

Research output: Contribution to journalArticlepeer-review

95 Citations (Scopus)

Abstract

Activating receptor activator of NF-kappaB (RANK) and TNF receptor (TNFR) promote osteoclast differentiation. A critical ligand contact site on the TNFR is partly conserved in RANK. Surface plasmon resonance studies showed that a peptide (WP9QY) that mimics this TNFR contact site and inhibits TNF-alpha-induced activity bound to RANK ligand (RANKL). Changing a single residue predicted to play an important role in the interaction reduced the binding significantly. WP9QY, but not the altered control peptide, inhibited the RANKL-induced activation of RANK-dependent signaling in RAW 264.7 cells but had no effect on M-CSF-induced activation of some of the same signaling events. WP9QY but not the control peptide also prevented RANKL-induced bone resorption and osteoclastogenesis, even when TNFRs were absent or blocked. In vivo, where both RANKL and TNF-alpha promote osteoclastogenesis, osteoclast activity, and bone loss, WP9QY prevented the increased osteoclastogenesis and bone loss induced in mice by ovariectomy or low dietary calcium, in the latter case in both wild-type and TNFR double-knockout mice. These results suggest that a peptide that mimics a TNFR ligand contact site blocks bone resorption by interfering with recruitment and activation of osteoclasts by both RANKL and TNF.
Original languageEnglish
Pages (from-to)1525-1534
Number of pages10
JournalThe Journal of Clinical Investigation
Volume116
Issue number6
DOIs
Publication statusPublished - 1 Jun 2006

Keywords

  • Amino Acid Sequence
  • Animals
  • Bone Resorption
  • Calcium, Dietary
  • Carrier Proteins
  • Cell Line
  • Cells, Cultured
  • Female
  • Glycoproteins
  • Lumbar Vertebrae
  • Male
  • Membrane Glycoproteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Molecular
  • Molecular Sequence Data
  • Osteoclasts
  • Osteoprotegerin
  • Ovariectomy
  • Peptides
  • Protein Conformation
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Tumor Necrosis Factor
  • Sequence Alignment
  • Signal Transduction
  • Tumor Necrosis Factor-alpha

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