Basic research focused on solving the clinical problems of bone metabolism regulated by transcription factor NF-κB: My personal historical narrative about the role of NF-κB in bone metabolism

Abstract

Nuclear factor-κB (NF-κB) is a transcription factor that regulates gene expression during inflammatory and immune responses. NF-κB signaling pathways are also important for bone homeostasis, particularly for osteoclast differentiation. A selective NF-κB inhibitor blocked the receptor activator of NF-κB ligand (RANKL)-stimulated NF-κB activation and osteoclastogenesis both in vitro and in vivo. Furthermore, alymphoplasia (aly/aly) mice, in which the processing of p100 to p52 does not occur because of an inactive form of NF-κB-inducing kinase (NIK), showed mild osteopetrosis with significantly reduced osteoclast numbers. In contrast, recent findings also showed that the inactivation of NF-κB enhanced osteoblast differentiation in vitro and in vivo, suggesting that NF-κB regulates osteoclastic bone resorption as well as osteoblastic bone formation. In addition, NF-κB is constitutively activated in many cancers, including oral squamous cell carcinoma (OSCC), and is involved in the invasive characteristics of OSCC. A selective NF-κB inhibitor suppressed zygoma and mandible destruction induced by OSCC, and reduced the number of osteoclasts in an animal model. Taken together, the inhibition of NF-κB is useful for inhibiting bone destruction, e.g., that caused by arthritis, osteoporosis, and bone invasion by OSCC, and for promoting bone regeneration by stimulating osteoblastic bone formation.