2025/04/22 by Masataka Anzai, Miho Watanabe‐Takahashi, Hiroshi Kawabata +8 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Bone Metabolism and Diseases #NF-κB Signaling Pathways #Cytokine Signaling Pathways and Interactions
paper · pdf · doi:10.1038/s42003-025-08047-2
openalex publication_date 2025/04/22 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/03
Bone-destructive diseases are caused by dysregulated osteoclastogenesis. Osteoclast differentiation is positively regulated by the ligand for receptor activator of nuclear factor kappa B (RANKL) binding to the RANK on progenitor cells. RANK then forms a multivalent interaction with an adapter molecule, tumor necrosis factor receptor-associated factor 6 (TRAF6), to transduce various downstream signals. We used affinity-based screening of a multivalent random-peptide library to identify a tetravalent peptide, WHD-tet, that binds to the RANK-binding region of TRAF6 through a multivalent interaction. CR4-WHD-tet, a cell-permeable form of WHD-tet, efficiently inhibited the RANKL-induced differentiation of bone-marrow cells to osteoclasts and osteoclastogenesis in a mouse model. CR4-WHD-tet specifically inhibited the recruitment of MAPK kinase 3 to TRAF6 without affecting other signal transducers in a late stage of differentiation, inhibiting the activation of p38-MAPK, which promotes the final stage. Thus, the interaction modulator CR4-WHD-tet fine-tunes the formation of a critical signaling complex to inhibit osteoclastogenesis. A tetravalent peptide can finely modulate the multivalent interaction between RANK and TRAF6 to inhibit osteoclastogenesis by specifically inhibiting the recruitment of MAPK kinase 3 to TRAF6 without affecting other signal transducers.