[NF-kappaB signaling pathways and the future perspectives of bone disease therapy using selective inhibitors of NF-kappaB].

The transcriptional factor nuclear factor kappaB(NF-kappaB)regulates the expression of a wide variety of genes that are involved in immune and inflammatory responses, proliferation, and tumorigenesis. NF-kappaB consists of five members, such as p65(RelA), RelB, c-Rel, p50/p105(NF-kappaB1), and p52/p100(NF-kappaB2). There are two distinct NF-kappaB activation pathways, termed the classical and alternative NF-kappaB signaling pathways. Since mice lacking both p50 and p52 subunits developed typical osteopetrosis, due to total lack of osteoclasts, NF-kappaB is also important osteoclast differentiation. A selective NF-kappaB inhibitor blocked receptor activator of NF-kappaB ligand(RANKL)-induced osteoclastogenesis both in vitro and in vivo. Recent findings have shown that inactivation of NF-kappaB enhances osteoblast differentiation in vitro and bone formation in vivo. NF-kappaB is constitutively activated in many cancers including oral squamous cell carcinoma(OSCC), and is involved in the invasive characteristics of OSCC. A selective NF-kappaB inhibitor also prevented jaw bone destruction by OSCC by reduced osteoclast numbers in animal model. Thus the inhibition of NF-kappaB might useful for the treatment of bone diseases, such as arthritis, osteoporosis, periodontitis, and bone invasion by OSCC by inhibiting bone resorption and by stimulating bone formation.