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Osteoclasts are unique multinucleated cells that can resorb bone. Bone mass is determined by a tightly regulated balance between osteoclasts and osteoblasts, which generate bones. Thus, the excessive formation of osteoclasts leads to the pathological bone resorption observed in postmenopausal osteoporosis, rheumatoid arthritis, Paget’s disease, and bone tumor metastases. During osteoclast differentiation, NF-κB is activated by TRAF6-mediated signals from RANK expressed on the surface of osteoclast progenitor cells upon RANKL stimulation, activating NFATc1, a master transcription factor in osteoclastogenesis. However, in contrast regular NF-κB activation, sufficient NFATc1 activation requires long-term activation of NF-κB, which can be induced uniquely by RANK but not by CD40, a receptor that also uses TRAF6 to activate NF-κB. Through analysis of various RANK mutants, we identified the 60-amino-acid HCR domain (mouse RANK) in the cytoplasmic tail of RANK. HCR is highly conserved among vertebrates and is crucial for long-term NF-κB activation. Interestingly, when HCR was attached to the cytoplasmic tail of CD40, the chimeric receptor promoted osteoclast formation, even though CD40 itself cannot. In this chapter, we explore the molecular mechanisms of HCR-mediated signals and the possible application of the HCR peptide as an anti-bone-resorptive drug.

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Taguchi, Y., Gohda, J., Inoue, Ji. (2015). NF-κB Signaling in Osteoclastogenesis. In: Inoue, Ji., Takekawa, M. (eds) Protein Modifications in Pathogenic Dysregulation of Signaling. Springer, Tokyo.

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