NF-κB signaling and bone resorption

Abstract

The transcription factor NF-κB is a family of proteins involved in signaling pathways essential for normal cellular functions and development. Deletion of various components of this pathway resulted with abnormal skeletal development. Research in the last decade has established that NF-κB signaling mediates RANK ligand-induced osteoclastogenesis. Consistently, it was shown that inhibition of NF-κB was an effective approach to inhibit osteoclast formation and bone resorptive activity. Identification of the molecular machinery underlying NF-κB activation permitted osteoclast-specific deletion of the major components of this pathway. As a result, it was clear that deletion of members of the proximal IKK kinase complex and the distal NF-κB subunits and downstream regulators affected skeletal development. These studies provided several targets of therapeutic intervention in osteolytic diseases. NF-κB activity has been also described as the centerpiece of inflammatory responses and is considered a potent mediator of inflammatory osteolysis. Indeed, inflammatory insults exacerbate physiologic RANKL-induced NF-κB signals leading to exaggerated responses and to inflammatory osteolysis. These superimposed NF-κB activities appear to underlie several bone pathologies. This review will describe the individual roles of NF-κB molecules in bone resorption and inflammatory osteolysis.

Fig. 1

Illustration of NF-κB signaling pathway depicting classical and alternative arms. Ligand (L) binding to its cell membrane (CM) receptor (R) initiates recruitment and formation of a signaling cluster at the distal end of the receptor. Signaling complexes contain a large number of proteins including TNF receptor-associated factors (TRAFs), the tyrosine kinase c-Src, p62, cellular inhibitors of apoptosis (c-IAP), and TNF receptor-interacting protein (RIP). This cluster utilizes lysine 63-linked polyubiquitination chains (K63-pUB) to recruit and activate the MAP kinases TGF-β-activated kinase (TAK1) and NF-κB-inducing kinase (NIK) which in turn activate the canonical and alternative IKK complexes, respectively. Activated IKK1 and IKK2 phosphorylate (pp) their respective p100/NF-kB and IkB targets, which are subsequently degraded. Processed p52 along with RelB as well as liberated p50/p65 dimers translocate to the nucleus (Nuc), bind to DNA sequences, and activate transcription. L ligand, R receptor, CM cytoplasmic membrane, Nuc nucleus, p phosphorylation