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<p>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.</p>

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Clustered peptide regulating the multivalent interaction between RANK and TRAF6 inhibits osteoclastogenesis by fine-tuning signals

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月22日

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  • Masataka Anzai,
  • Miho Watanabe-Takahashi,
  • Hiroshi Kawabata,
  • Yuri Masuda,
  • Aoi Ikegami,
  • Yuta Okuda,
  • Tsuyoshi Waku,
  • Hiroaki Sakurai,
  • Keizo Nishikawa,
  • Jun-ichiro Inoue,
  • Kiyotaka Nishikawa

摘要

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.