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A TNF receptor loop peptide mimic blocks RANK ligand–induced signaling, bone resorption, and bone loss
Kazuhiro Aoki, … , William C. Horne, Roland Baron
Kazuhiro Aoki, … , William C. Horne, Roland Baron
Published June 1, 2006
Citation Information: J Clin Invest. 2006;116(6):1525-1534. https://doi.org/10.1172/JCI22513.
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Research Article Bone biology Article has an altmetric score of 9

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

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Abstract

Activating receptor activator of NF-κB (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-α–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-α 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.

Authors

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

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Figure 6

WP9QY inhibits osteoclastogenesis in bone marrow cultures when TNFRs are missing or blocked.

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WP9QY inhibits osteoclastogenesis in bone marrow cultures when TNFRs are...
(A) Bone marrow cells from mice that lacked either TNFR(I) (p55–/–) or TNFR(II) (p75–/–) or their wild-type littermates were cultured with M-CSF (30 ng/ml) and sRANKL (30 ng/ml), with or without WP9QY (5 μM). In all cases, WP9QY reduced the number of TRAP+ multinucleated cells (MNCs) by more than 80% (*P < 0.001 relative to matched untreated culture). The results are representative of 2 independent experiments. (B) Bone marrow cells from mice that lacked p55 were cultured with an antibody that blocked p75 and increasing concentrations of WP9QY (μM) as indicated. The antibody had little additional effect on the number of TRAP+ MNCs produced. All concentrations of WP9QY efficiently inhibited the sRANKL-induced osteoclastogenesis (*P < 0.001 relative to culture with anti-p75 antibody). The results are representative of 2 independent experiments. (C) Bone marrow cells from mice that lacked p75 were cultured with an antibody that blocked p55 and increasing concentrations of WP9QY as indicated. In contrast to the lack of effect of anti-p75 in the p55–/– marrow cultures, anti-p55 significantly reduced the TRAP+ MNC formation from p75–/– bone marrow cells. WP9QY further inhibited TRAP+ MNC formation in a dose-dependent manner (#P < 0.001 relative to the cultures in the absence of anti-p55; ##P < 0.02 relative to culture in the presence of anti-p55; **P < 0.001 relative to culture in the presence of anti-p55). The results are representative of 2 independent experiments.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 10 patents
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