The Role of NF-κB in Physiological Bone Development and Inflammatory Bone Diseases: Is NF-κB Inhibition Killing Two Birds with One Stone?

Nuclear factor-kappa B (NF-kappa B) is a transcription factor that regulates the expression of various genes involved in inflammation and the immune response. The activation of NF-kappa B occurs via two pathways: inflammatory cytokines, such as TNF-alpha and IL-1 beta, activate the classical pathway, and cytokines involved in lymph node formation, such as CD40L, activate the alternative pathway. NF-kappa B1 (p50) and NF-kappa B2 (p52) double-knockout mice exhibited severe osteopetrosis due to the total lack of osteoclasts, suggesting that NF-kappa B activation is required for osteoclast differentiation. These results indicate that NF-kappa B may be a therapeutic target for inflammatory bone diseases, such as rheumatoid arthritis and periodontal disease. On the other hand, mice that express the dominant negative form of I kappa B kinase (IKK)-beta specifically in osteoblasts exhibited increased bone mass, but there was no change in osteoclast numbers. Therefore, inhibition of NF-kappa B is thought to promote bone formation. Taken together, the inhibition of NF-kappa B leads to killing two birds with one stone: it suppresses bone resorption and promotes bone formation. This review describes the role of NF-kappa B in physiological bone metabolism, pathologic bone destruction, and bone regeneration.