Required and nonessential functions of nuclear factor-kappa B in bone cells

Nuclear factor-kappa B (NF-kappa B) is a set of five polypeptide transcript ion factors, called p50, p52, p65 (also called Rel A), Rel B, and c-Rel, wh ich regulate the expression of a variety of genes involved in immune and in flammatory responses, They were originally named because they were consider ed essential regulators of B cell kappa light chain expression. More recent studies indicate that NF-kappa B proteins are involved in the regulation o f a variety of other cell functions, including cell proliferation, response s to stress, and apoptosis, NF-kappa B heterodimers reside in the cytoplasm of cells bound to inhibitory proteins, the two commonest of which are I ka ppa B alpha and I kappa B beta, which prevent NF-kappa B from entering the nucleus. When cells are stimulated, I kappa B is phosphorylated by specific I kappa B kinases and subsequently is ubiquitinated and degraded in proteo somes, This allows NF-kappa B to translocate to the nucleus to regulate the expression of a growing list of genes, including the proinflammatory cytok ines, interleukin-1 (IL-1), IL-6, and tumor necrosis factor. IL-1 and tumor necrosis factor in turn also regulate the expression of NF-kappa B, Thus, once activated, NF-kappa B may be involved in upregulatory loops, which can amplify the effects of the initiating stimulus, Because these proinflammat ory cytokines have been implicated in the pathogenesis of estrogen deficien cy and inflammation-related bone loss, it is likely that NF-kappa B has a s ignificant role in the increased generation and function of osteoclasts in these circumstances. However, an unexpected and essential role of NF-kappa B in the formation of osteoclasts during development was discovered recentl y after the generation of knockout mice, which lack the expression of the p 50 and p52 subunits, This paper Kill describe recent studies that reveal an essential role for NF-kappa B signaling in the generation of osteoclasts a nd that suggest that NF-kappa B may also play a key central role in the act ivation and survival of osteoclasts in conditions in which osteoclastogenes is is upregulated, (C) 1999 by Elsevier Science Inc. All rights reserved.