Inhibition of RANKL-mediated osteoclast differentiation by selective TRAF6 decoy peptides.
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.
Poblenz
Ann T
AT
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Box 143, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Jacoby
Joerg J
JJ
Singh
Sujay
S
Darnay
Bryant G
BG
D000595:Amino Acid Sequence; D000818:Animals; D001862:Bone Resorption / Q000473:pathology / Q000517:prevention & control; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D053245:RANK Ligand / Q000494:pharmacology*; D047992:TNF Receptor-Associated Factor 2 / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D048015:TNF Receptor-Associated Factor 5 / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D048029:TNF Receptor-Associated Factor 6 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors
D010446:Peptide Fragments; D053245:RANK Ligand; D047992:TNF Receptor-Associated Factor 2; D048015:TNF Receptor-Associated Factor 5; D048029:TNF Receptor-Associated Factor 6