A Novel Receptor Activator of NF-κB (RANK) Cytoplasmic Motif Plays an Essential Role in Osteoclastogenesis by Committing Macrophages to the Osteoclast Lineage

Duorong Xu,Shunqing Wang,Wei Liu,Jianzhong Liu,Xu Feng

doi:10.1074/jbc.m510383200

Abstract

Receptor activator of NF-kappaB (RANK) ligand (RANKL) and its receptor RANK play an essential role in osteoclastogenesis and osteoclast function by activating several signaling pathways. However, several lines of evidence suggest that RANK also transmits an unidentified signaling pathway(s) essential for osteoclastogenesis. To identify the novel pathway(s), we carried out a detailed structure/function study of the RANK cytoplasmic domain. A series of studies using numerous deletion/point mutants elucidated a specific 4-amino acid motif (535IVVY538) essential for osteoclastogenesis. This novel motif plays a crucial role in committing macrophages to the osteoclast lineage but is not implicated in osteoclast function or survival. Moreover, this motif does not activate the known RANK signaling pathways, indicating that it initiates a novel pathway(s). The identification of the novel motif not only provides critical insight into RANK signaling in osteoclastogenesis, but more importantly, the RANK motif and its downstream signaling pathways may represent specific therapeutic targets for various bone diseases, including postmenopausal osteoporosis.

Highlights

In bone, RANKL is an essential regulator of osteoclast formation and a potent modulator of osteoclast function and survival (5, 8, 9)
Identification of a 40-aa RANK Intracellular Segment Essential for Osteoclastogenesis—Previously, we reported the characterization of three functional TNF receptor-associated factors (TRAFs) binding motifs in the RANK cytoplasmic domain by using a chimeric receptor consisting of mouse TNFR1 external domain linked to the transmembrane and intracellular domains of mouse RANK (23)
The Novel RANK Motif Is Not Involved in Osteoclast Function or Survival—Above we have shown that the novel motif plays an essential role in osteoclastogenesis by committing macrophages to the osteoclast lineage, suggesting that this novel motif may not be involved in osteoclast function and survival

Summary

Introduction

RANKL is an essential regulator of osteoclast formation (osteoclastogenesis) and a potent modulator of osteoclast function and survival (5, 8, 9). Through these functional TRAF binding motifs, RANK activates six major signaling pathways NF-␬B, JNK, ERK, p38, NFATc1, and Akt, which play important roles in osteoclast formation, function and/or survival (8, 9, 23, 25).

Results

Conclusion