On page 1677, Ruocco et al. show that the formation of bone-resorbing osteoclasts is crippled when the β subunit of the NF-κB–activating IκB kinase (IKK) complex is missing. The absence of IKKβ also protected mice against inflammatory-induced bone loss, a complication of inflammatory diseases such as rheumatoid arthritis (RA) that is caused by excessive activation of osteoclasts.

The β subunit of the IκB kinase complex is required for inflammation-induced bone loss (arrows).

The osteoclast growth factor RANKL (receptor activator of NF-κB ligand) activates the transcription factor NF-κB, which promotes osteoclast development. NF-κB activation requires the upstream IKK complex (IKKα, β, γ), which releases NF-κB from its inhibitor protein. Although a recent report showed that the IKK complex is required for osteoclast development, the relative importance of the two catalytic subunits of IKK (α, β) in this process remained unclear.

Ruocco et al. now show that mice lacking IKKβ were unable to generate osteoclasts and developed severe osteopetrosis (increased bone formation), whereas those lacking IKKα activity had no apparent bone abnormalities. The IKKβ-deficient mice failed to transmit RANKL signals and had increased TNF-induced apoptosis in osteoclast precursors. Osteoclast formation was partially restored in mice that lacked both IKKβ and the type I TNF receptor.

IKKβ-deficient mice were also resistant to inflammatory bone loss and this resistance was dependent on TNF-derived signals. Thus the authors suggest that drugs designed to block IKKβ may prevent bone loss in patients. However, they caution that such drugs, if developed, should perhaps not be combined with anti-TNF therapy (commonly used to treat RA) as the combination may not be effective.