Bone undergoes a continuous cycle of renewal, and osteoclasts — the cells responsible for bone resorption — play a pivotal role in bone homeostasis. This resorption is largely mediated by inflammatory cytokines such as TNF-α. In this issue of the JCI, Yao et al. demonstrate that the NF-κB precursor protein NF-κB2 (p100) acts as a negative regulator of osteoclastogenesis (see the related article beginning on page 3024). TNF-α induced a sustained accumulation of p100 in osteoclast precursors, and TNF-α–induced osteoclast formation was markedly increased in Nfkb2–/– mice. They also found that TNF receptor–associated factor 3 (TRAF3) is involved in the posttranslational regulation of p100 expression. These results suggest that blockade of the processing of p100 is a novel strategy to treat TNF-α–related bone diseases such as RA.
Sakae Tanaka, Hiroyasu Nakano
Schematic representation of RANKL and TNF-α–induced signaling in osteoclast precursors.