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Copyright ©2012 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Orthop. Nov 18, 2012; 3(11): 167-174
Published online Nov 18, 2012. doi: 10.5312/wjo.v3.i11.167
Molecular mechanisms of triggering, amplifying and targeting RANK signaling in osteoclasts
Yukiko Kuroda, Koichi Matsuo
Yukiko Kuroda, Koichi Matsuo, Laboratory of Cell and Tissue Biology, School of Medicine, Keio University, Tokyo 160-8582, Japan
Author contributions: Kuroda Y and Matsuo K performed literature review and prepared the manuscript.
Supported by Grants from MEXT Japan, No. 23790265 (to Kuroda Y) and No. 21390425 (to Matsuo K)
Correspondence to: Koichi Matsuo, MD, PhD, Professor, Laboratory of Cell and Tissue Biology, School of Medicine, Keio University, Tokyo 160-8582, Japan.
Telephone: +81-3-33531211 Fax: +81-3-33530530
Received: June 20, 2012
Revised: October 25, 2012
Accepted: November 1, 2012
Published online: November 18, 2012

Osteoclast differentiation depends on receptor activator of nuclear factor-κB (RANK) signaling, which can be divided into triggering, amplifying and targeting phases based on how active the master regulator nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) is. The triggering phase is characterized by immediate-early RANK signaling induced by RANK ligand (RANKL) stimulation mediated by three adaptor proteins, tumor necrosis factor receptor-associated factor 6, Grb-2-associated binder-2 and phospholipase C (PLC)γ2, leading to activation of IκB kinase, mitogen-activated protein kinases and the transcription factors nuclear factor (NF)-κB and activator protein-1 (AP-1). Mice lacking NF-κB p50/p52 or the AP-1 subunit c-Fos (encoded by Fos) exhibit severe osteopetrosis due to a differentiation block in the osteoclast lineage. The amplification phase occurs about 24 h later in a RANKL-induced osteoclastogenic culture when Ca2+ oscillation starts and the transcription factor NFATc1 is abundantly produced. In addition to Ca2+ oscillation-dependent nuclear translocation and transcriptional auto-induction of NFATc1, a Ca2+ oscillation-independent, osteoblast-dependent mechanism stabilizes NFATc1 protein in differentiating osteoclasts. Osteoclast precursors lacking PLCγ2, inositol-1,4,5-trisphosphate receptors, regulator of G-protein signaling 10, or NFATc1 show an impaired transition from the triggering to amplifying phases. The final targeting phase is mediated by activation of numerous NFATc1 target genes responsible for cell-cell fusion and regulation of bone-resorptive function. This review focuses on molecular mechanisms for each of the three phases of RANK signaling during osteoclast differentiation.

Keywords: Receptor activator of nuclear factor-κB ligand, Tumor necrosis factor receptor-associated factor 6, c-Fos, Nuclear factor of activated T-cells cytoplasmic 1, Immunoreceptor tyrosine-based activation motif, Ca2+ oscillation