Impediment of NEMO oligomerization inhibits osteoclastogenesis and osteolysis

Isra Darwech, Jesse Otero, Muhammad Alhawagri, Simon Dai, Yousef Abu-Amer

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

The transcription factor NF-κB is essential for osteoclastogenesis and is considered an immune-modulator of rheumatoid arthritis and inflammatory osteolysis. Activation of NF-κB subunits is regulated by the upstream IkB kinase (IKK) complex which contains IKKα, IKKβ, and IKKγ; the latter also known as NF-κB essential modulator (NEMO). The role of IKKα and IKKβ in the skeletal development and inflammatory osteolysis has been described, whereas little is known regarding the role of NEMO in this setting. Typically, signals induced by RANK ligand (RANKL) or TNF prompt oligomerization of NEMO monomers through the coiled-coil-2 (CC2) and leucine zipper (LZ) motifs. This step facilitates binding to IKKs and further relaying signal transduction. Given the central role of NF-κB in osteoclastogenesis, we asked whether NEMO is essential for osteoclastogenesis and whether interruption of NEMO oligomerization impedes osteoclast differentiation in vitro and in vivo. Using cell-permeable short peptides overlapping the CC2 and LZ motifs we show that these peptides specifically bind to NEMO monomers, prevent trimer formation, and render NEMO monomers susceptible for ubiquitin-mediated degradation. Further, CC2 and LZ peptides attenuate RANKL- and TNF-induced NF-κB signaling in bone marrow-derived osteoclast precursors (OCPs). More importantly, these peptides potently inhibit osteoclastogenesis, in vitro, and arrest RANKL-induced osteolysis, in mice. To further ascertain its role in osteoclastogenesis, we were able to block osteoclastogenesis using NEMO siRNA knockdown approach. Collectively, our data establish that obstruction of NEMO oligomerization destabilizes NEMO monomers, inhibits NF-κB activation, impedes osteoclastogenesis and arrests inflammatory osteolysis. Thus, NEMO presents itself as a promising target for anti-osteolytic intervention.

Original languageEnglish
Pages (from-to)1337-1345
Number of pages9
JournalJournal of cellular biochemistry
Volume108
Issue number6
DOIs
StatePublished - Dec 15 2009

Keywords

  • Coiled-coil
  • Leucine zipper
  • NEMO/IKKγ
  • NF-κB
  • Osteoclast
  • Osteolysis

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