The transcription factor NF-kappaB is essential for osteoclastogenesis and is 
considered an immune-modulator of rheumatoid arthritis and inflammatory 
osteolysis. Activation of NF-kappaB subunits is regulated by the upstream 
IkappaB kinase (IKK) complex which contains IKKalpha, IKKbeta, and IKKgamma; the 
latter also known as NF-kappaB essential modulator (NEMO). The role of IKKalpha 
and IKKbeta 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-kappaB 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-kappaB 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-kappaB activation, impedes 
osteoclastogenesis and arrests inflammatory osteolysis. Thus, NEMO presents 
itself as a promising target for anti-osteolytic intervention.