The role of nuclear factor-κB signaling in bone formation: One bite provides dual tastes

Background Nuclear factor-κB (NF-κB) is a transcription factor that regulates a wide range of gene expression events during inflammatory and immune responses. Gene targeting of NF-κB1 and NF-κB2 has revealed that NF-κB plays a critical role in osteoclastogenesis. However, recent findings have also shown that inactivation of NF-κB enhances osteoblast differentiation both in vitro and in vivo, suggesting that NF-κB regulates osteoblastic bone formation as well as osteoclastic bone resorption. Highlight Two different NF-κB signaling pathways, the "classical" and "alternative" pathways, enhance bone formation through distinct mechanisms. First, p65, the main subunit of the classical pathway, binds the Smad1/Smad4 complex and facilitates interference with the DNA-binding activity of Smad proteins, induced by bone morphogenetic protein (BMP). Second, the processing from p100 to p52 in the alternative pathway negatively regulates BMP2-induced Smad phosphorylation and alkaline phosphatase activity by modulating the expression of the BMP type I receptor ALK2. Conclusion Collectively, the data suggest that the inhibition of NF-κB is useful not only for inhibiting bone resorption but also for promoting bone formation, thus explaining the notion "one bite gets two tastes." We believe that NF-κB-selective inhibitors may have the potential to improve BMP-induced bone regeneration.